Method and apparatus for noninvasively monitoring parameters of a region of interest in a human body

ABSTRACT

A method and system for noninvasive monitoring of at least one parameter of a region of interest in a human body. The system comprises a measurement unit and a control unit. The measurement unit comprises an optical unit having an illumination assembly ( 101 A) and a light detection assembly ( 101 B) to generate measured data indicative of collected light; and an acoustic unit ( 110 ) configured to generate acoustic waves of a predetermined ultrasound frequency range. The measurement unit provides an operating condition such that the acoustic waves overlap with an illuminating region within the region of interest and substantially do not overlap outside the region of interest. The measured data is indicative of scattered light having both ultrasound tagged and untagged light portions, enabling to distinguish between light responses of the region of interest and the region outside the region of interest.

FIELD OF THE INVENTION

This invention relates to a method and apparatus for noninvasivemonitoring of parameters of a region of interest in a human body, suchas oxygen saturation and/or concentration of analyte(s) in blood.

BACKGROUND OF THE INVENTION

Monitoring of the well-being of the fetus inside the uterus is veryimportant and is carried periodically with respect to various parametersof the fetus. One of the important parameters to be monitored is oxygensaturation. Various techniques have been developed to enable noninvasivemeasurements of oxygen saturation.

For example, U.S. Pat. No. 5,494,032 discloses an oximeter for reliableclinical determination of blood oxygen saturation in a fetus. Thistechnique utilizes a multiple frequency light source which is coupled toan optical fiber. The output of the fiber is used to illuminate bloodcontaining tissue of the fetus. The reflected light is transmitted backto the apparatus where the light intensities are simultaneously detectedat multiple frequencies. The resulting spectrum is then analyzed fordetermination of oxygen saturation. The analysis method usesmultivariate calibration techniques that compensate for nonlinearspectral response, model interfering spectral responses and detectoutlier data with high sensitivity.

A pulse oximetry based technique for determining the fetal arterialblood oxygenation is disclosed in the following article: A. Zourabian etal., “Trans-abdominal monitoring of fetal arterial blood oxygenationusing pulse oxymetry”, Journal of Biomedical Optics, Vol. 5, No. 4,October 2000, pp. 391-405.

U.S. Pat. No. 6,041,248 describes a method and apparatus for frequencyencoded ultrasound-modulated optical tomography of dense turbid media.The apparatus includes a function generator producing a frequency sweepsignal which is applied to an ultrasonic transducer. The ultrasonictransducer produces ultrasonic wave in a turbid medium. Coherent lightfrom a laser is passed through turbid medium where it is modulated bythe ultrasonic wave. A photomultiplier tube detects the light whichpasses through the turbid medium. The signal from the photomultipliertube is fed to an oscilloscope and then to a computer where differencesin light intensity at different frequencies can determine the locationof objects in the turbid medium.

The conventionally used techniques for monitoring the well-being of thefetus inside the uterus utilize measuring the fetal-heart-rate (FHR) byplacing sensors on the skin of the mother's abdomen proximal to thefetus. These sensors transmit acoustic waves and provide data indicativeof the Doppler shift of an acoustic wave reflected from the fetal heart,enabling calculation of the heart rate based on this shift. A normalfetal-heart-rate (FHR) pattern is usually associated with the deliveryof a normal well-oxygenated infant. However, a non-reassuring FHR is notalways associated with the delivery of a compromised infant.

In the case of non-reassuring FHR, the fetal blood oxygen saturationlevel can be measured only post membrane rupture by either fetal scalpsampling, which measures the pH level of the fetal blood, or byattaching a pulse oximeter to the presenting part of the fetal headduring labor. Both of these methods are performed following the ruptureof membranes where the fetal scalp and/or cheeks can be reached.

Another important procedure to be done to monitor the well-being of thefetus consists of assessing the maturity of fetal lungs, which is one ofthe major concerns of pre-term deliveries. If the baby is delivered andthe lungs are not mature, the baby may develop Respiratory DistressSyndrome (RDS), which can result either in fetal death or inlong-lasting periods of repeated respiratory difficulty.

In cases where intervention is considered in the course of pregnancy(such as caesarean section or induction of labor) and there is a need toassess the maturity of the lungs, amniotic fluid is drained. Measuringphospholipids in amniotic fluid as the lecithin/sphingomyelin ratiousing the thin-layer chromatography method has been the establishedclinical procedure for predicting fetal lung maturity. Although it isthe clinical “gold standard” method, it remains a time-consumingprocess, has a large intralaboratory and interlaboratory coefficient ofvariation, and requires expertise. In addition, the procedure ofamniotic fluid drainage itself is invasive and suffers a small risk ofabortion. Additional techniques that are used for assessing lungmaturity levels include measuring the number of lamellar bodies in avolume of amniotic fluid, measuring the prostaglandin level in amnioticfluid and measuring the fluorescence polarization of a sampled amnioticfluid.

When a fetus is acutely distressed, for example as a result ofstrangulation by the umbilical cord, the bowel content, meconium, may bepassed into the amniotic fluid (AF). Assessment of meconialcontamination of AF is important in the management of late pregnancy. Itappears in nearly one third of all fetuses by 42 weeks of gestation. Incases where the fetus gasps during delivery, inhaling the stickymeconium into the upper respiratory tract results in partial airwaysobstruction. Meconium aspiration syndrome occurs in 0.2% to 1% of alldeliveries and has a mortality rate as high as 18%. The disease isresponsible for 2% of all prenatal deaths.

To date, meconium stained amniotic fluid is diagnosed following therupture of membranes, when the amniotic fluid is drained. However, incases where the fetus head is tightly fitted in the pelvis, the amnioticfluid is not drained out resulting in misdiagnosis of the potentialharmful outcome to the respiratory tract.

SUMMARY OF THE INVENTION

There is accordingly a need in the art to facilitate noninvasivemonitoring of parameters of a region of interest in a human body, byproviding a novel noninvasive method and apparatus.

The technique of the present invention provides for monitoring bloodand/or tissue parameters and/or parameters of fluids of a region ofinterest in a human body, for example the concentration of an analyte inblood, fluid reservoirs or tissue regions in a human body; as well asfetus condition in utero (e.g., the fetal oxygen saturation level aswell as the concentration of analyte in fetal blood; and the maturity offetal lungs and the presence of meconium, prior to membrane rupture).

It should be understood that the term “region of interest” signifies atissues region or a fluid contained in a reservoir or cavity inside abody. The region of interest may be a fetus region (e.g., fetus head),amniotic fluid, vicinity of blood vessels, etc. The term “fetus-relatedregion of interest” used herein signifies either one of fetus andamniotic fluid regions.

The main idea of the present invention consists of non-invasivelymonitoring the optical properties of a region of interest in a human (oranimal) body utilizing the principles of ultrasound tagging of light,which in the present invention is aimed at distinguishing betweenoptical responses of the region of interest in the selected volume(e.g., fetus, amniotic fluid, blood vessel) and the surroundings outsidethe region of interest; and/or significantly improving pulse oximetrybased measurements.

According to one aspect of the present invention, a body portion (e.g.,the abdomen of a pregnant woman) containing a region of interest (fetus)is irradiated with light (e.g., of at least two different wavelengths)and is irradiated with acoustic waves, in a manner to ensure optimaloperating condition for measurements. This operating condition is suchthat the illuminating light and acoustic waves overlap within the regionof interest and thus light scattered from the region of interest is“tagged” by acoustic waves (i.e., the frequency of light is modulated bythe frequency of the acoustic waves) while substantially do not overlapin a region outside the region of interest, and to ensure that detectedlight includes a portion of light scattered by the region of interestand tagged by acoustic waves and a portion of untagged light scatteredby the region outside the region of interest. This allows fordistinguishing between light responses of the region of interest and itssurroundings (e.g., fetus and maternal tissues). It should be understoodthat the term “acoustic wave” refer to acoustic radiation of either oneof the following type: continuous wave, pulses, bursts.

It should be understood that for the purposes of the present inventionthe term “maternal tissues” used herein refers to all the tissues withina region surrounding the fetus-related region of interest (fetus itselfor amniotic fluid containing the fetus). Considering the region ofinterest is fetus, the term “maternal tissues” refers to maternaltissues, amniotic fluid, and uterine wall.

According to another aspect of the present invention, the aboveoperating condition is used in pulse oximetry measurements fordetermining oxygen saturation level in a region of interest (inmammalian blood and/or blood vessels). Measured data that needs to beanalyzed is, for example, in the form of a power spectrum ofultrasound-tagged light response of the region of interest, which ispractically insensitive to minor movements of regions outside the regionof interest, while pure pulse oximetric measurements are highlysensitive to such movements.

Preferably, the present invention in either of its aspects utilizesobtaining of measured data in the form of time dependent and/orwavelength dependent variations of ultrasound-tagged light signals forat least two wavelengths of illuminating light.

The present invention provides for non-invasively determining suchparameters as oxygen saturation level in the region of interest (e.g.,fetus, blood vessel), concentration of a substance or a structure withinthe region of interest (e.g., fetus, amniotic fluid), the presence andconcentration of lamellar bodies in amniotic fluid for determining thelevel of lung maturity of the fetus, the presence and/or concentrationof meconium in the amniotic fluid, presence and/or concentration ofblood in the amniotic fluid; as well as for noninvasive monitoring theoptical properties of other extravascular fluids such as pleural,pericardial, peritoneal (around the abdominal and pelvis cavities) andsynovial fluids. It is important to note that according to theinvention, acoustic (ultrasound) radiation used for measurements needsnot be focused, since the measurements utilize ultrasound tagging solelyfor the purposes of distinguishing between light responses of the regionof interest and its surroundings, and/or for increasing signal to noiseratio of ultrasound tagging based measurements.

The present invention utilizes the principles of oximetry for processingthe measured data. Accordingly, the illumination with at least twodifferent wavelengths is applied. Preferably, the light response signalsare collected over a time period larger than a heart beat, and theprinciples of pulse oximetry are used to determine the oxygensaturation.

Preferably, a measurement unit (an illumination assembly, a lightdetection assembly, and an ultrasound transducer arrangement) is placedin close contact with the respective body portion (e.g., maternaltissues being in contact with amniotic sac containing a fetus). Asindicated above, the illumination assembly is configured and operable toilluminate the body portion with at least two wavelengths. Theultrasound transducer arrangement is configured and operable to transmitacoustic waves into the same volume from which the light detectorcollects scattered light.

The light detection assembly may be oriented for collecting both backscattered light and forward scattered light.

Preferably, the present invention utilizes ultrasound imaging, carriedout prior to measurements and aimed at determining optimal positioningof the illumination assembly, light detection assembly and acousticwaves propagation to thereby provide the operating condition formeasurements. The ultrasound imaging may and may not utilize the sameultrasound transducer arrangement that is used for measurements.Preferably, the invention also provides for using ultrasaound radiationfor determining such parameters of blood in the region of interest(e.g., fetus) as blood flow, tissue velocity profile, etc. To this end,reflections of ultrasound radiation from the irradiated region areanalyzed using any known suitable Doppler-based techniques. The incidentultrasound radiation may be in the form of continuous waves or pulses(gates).

According to an embodiment of the present invention maternal oxygensaturation level is detected using the same apparatus being used tomeasure fetal oxygen saturation level.

The present invention can be used for measuring in more than one fetuspresented inside the uterus. In this case, the oxygen saturation level(or other fetal parameters) of each fetus is measured independentlyusing the same apparatus; or several different apparatuses, one for eachfetus, all associated with the same control unit (data processing andanalyzing utility). Each fetus is located using an ultrasound imagingsystem, and the optimal arrangement of the light sources, detectors andultrasound transducers is determined for monitoring the oxygensaturation level of each fetus.

There is thus provided according to one aspect of the invention amonitoring system for use in non-invasively monitoring at least oneparameter of a region of interest in a human body, the systemcomprising:

-   -   a measurement unit comprising an optical unit having an        illumination assembly configured to define at least one output        port for illuminating light, and a light detection assembly        configured to define at least one light input port for        collecting light scattered from the illuminated body portion and        to generate measured data indicative of the collected light; and        an acoustic unit configured to generate acoustic waves of a        predetermined ultrasound frequency range; the measurement unit        being configured and operable to provide an operating condition        such that the acoustic waves of the predetermined frequency        range overlap with an illuminating region within the region of        interest and substantially do not overlap with a region outside        the region of interest, and that the detection assembly collects        light scattered from the region of interest and light scattered        from the region outside the region of interest, the measured        data being thereby indicative of scattered light having both        ultrasound tagged and untagged light portions, thereby enabling        to distinguish between light responses of the region of interest        and the region outside the region of interest;    -   a control unit, which is connectable to the optical unit and to        the acoustic unit to operate these units, the control unit being        responsive to the measured data and preprogrammed to process and        analyze the measured data to extract therefrom a data portion        associated with the light response of the region of interest and        determine said at least one parameter of the region of interest.

According to another aspect of the invention, there is provided amonitoring system for use in non-invasively monitoring at least oneparameter of a region of interest in a human body, the systemcomprising:

-   -   a measurement unit comprising an optical unit configured for        generating illuminating light and for collecting light and        generating measured data indicative of the collected light; and        an acoustic unit configured to generate unfocused acoustic waves        of a predetermined ultrasound frequency range; the measurement        unit being configured and operable to provide an operating        condition such that the acoustic waves of the predetermined        frequency range overlap with an illuminating region within the        region of interest while substantially not overlapping within a        region outside the region of interest, and that the detection        assembly collects light scattered from the region of interest        and light scattered from the region outside the region of        interest, the measured data being thereby indicative of        scattered light having both ultrasound tagged and untagged light        portions, thereby enabling to distinguish between light        responses of the region of interest and the region outside the        region of interest;    -   a control unit, which is connectable to the optical unit and to        the acoustic unit to operate these units, the control unit being        responsive to the measured data and preprogrammed to process and        analyze the measured data to extract therefrom a data portion        associated with the light response of the region of interest and        determine said at least one parameter of the region of interest.

According to yet another aspect of the invention, there is provided asystem for use in noninvasive monitoring at least one parameter of aregion of interest in a human body, the system comprising:

-   -   a measurement unit comprising an optical unit having an        illumination assembly configured to define at least one output        port for illuminating light, and a light detection assembly        configured to define at least one light input port for        collecting light and to generate measured data indicative of the        collected light; and an acoustic unit configured to generate        acoustic waves of a predetermined ultrasound frequency range;    -   a control unit, which is connectable to the optical unit and to        the acoustic unit to operate these units, the control unit being        responsive to the measured data and preprogrammed to process and        analyze the measured data to extract therefrom data indicative        of a light response of the region of interest and determine the        at least one desired parameter, the control unit being operable        to provide optimal positioning of the optical unit and the        acoustic unit to satisfy an operating condition for        measurements, said operating condition being such that acoustic        waves of the predetermined frequency range and illuminating        light overlap within the region of interest and substantially do        not overlap in a region outside the region of interest, and in        that the detection assembly collects the light scattered from        the region of interest and light scattered from the region        outside the region of interest; the measured data being thereby        indicative of scattered light having both ultrasound tagged and        untagged light portions, thereby enabling to analyze the        measured data to extract therefrom a data portion associated        with the light response of the region of interest and determine        said at least one parameter of the region of interest.

According to yet another aspect of the invention, there is provided aprobe device for use in a system for monitoring at least one parameterof a region of interest in a human body, the probe comprising: a supportstructure configured to contact a body portion, said support structurecarrying an array of at least two light output ports arranged in aspaced-apart relationship and being optically coupled to a light sourceassembly, an array of light input ports arranged in a spaced-apartrelationship and being optically coupled to a light detection assembly,and at least one acoustic output port of an acoustic unit, thearrangement of the light ports and the acoustic unit being such as toallow selection of at least one of said light output ports, at least oneof the light input ports and at least one of the acoustic output portssuch that acoustic waves of a predetermined frequency range coming fromsaid at least one selected acoustic output port and illuminating lightcoming from said at least one selected light output port overlap withina region of interest in the body, and in that said at least one lightinput port collects light scattered from the overlapping region andlight scattered from outside the region of interest.

According to yet another aspect of the invention, there is provided aprobe device for use in a system for monitoring at least one parameterof a region of interest in a human body, the probe comprising: a supportstructure configured to contact a body portion, said support structurecarrying at least one light output port optically coupled to a lightsource assembly, at least two light input ports optically coupled to alight detection assembly, and at least one acoustic output port of anacoustic unit, the arrangement of the light and acoustic ports beingsuch as to allow selection of the light and acoustic ports formeasurements such that, with the selected ports, acoustic waves of apredetermined frequency range and illuminating light overlap within aregion of interest in the body and that the at least one light inputport collects light scattered from the overlapping region and lightscattered from outside of the region of interest.

According to yet another aspect of the invention, there is provided aprobe device for use in a system for monitoring at least one parameterof a region of interest in a human body, the probe comprising: a supportstructure configured to contact a body portion, said support structurecarrying at least two light output port optically coupled to a lightsource assembly, at least one light input port optically coupled to alight detection assembly, and at least one acoustic output port of anacoustic unit, the arrangement of the light and acoustic ports beingsuch as to allow selection of the light and acoustic ports formeasurements such that, with the selected ports, acoustic waves of apredetermined frequency range and illuminating light overlap within aregion of interest in the body and that detected light includesscattered from the overlapping region and light scattered from outsideof the region of interest.

According to yet another aspect of the invention, there is provided amethod for use in noninvasive monitoring at least one parameter of aregion of interest in a human body, the method comprising: operating anoptical unit and an acoustic unit so as to provide that ultrasound wavesof a predetermined frequency range and illuminating light overlap withinthe region of interest and substantially do not overlap with a regionoutside the region of interest, thereby producing measured dataindicative of collected light including scattered light havingultrasound tagged and untagged light portions, thereby enablingextraction of a light response of the region of interest from all theother light portions in the collected light.

According to yet another aspect of the invention, there is provided amethod for use in noninvasive monitoring oxygen saturation level, themethod comprising: applying ultrasound tagging of light in pulseoxymetric measurements, obtaining measured data indicative of timedependent variations of ultrasound tagged light signals scattered from aregion of interest as a function of at least one of time and for atleast two different wavelength of illuminating light, and analyzing themeasured data to calculate the oxygen saturation level.

According to yet another aspect of the invention, there is provided amethod for use in noninvasive monitoring at least one parameter of aregion of interest in a human body, the method comprising:

-   -   providing an optical unit having an illumination assembly        configured to define at least one output port for illuminating        light; and a light detection assembly configured to define at        least one light input port for collecting light, and to generate        measured data indicative of the collected light; and providing        an acoustic unit configured to generate acoustic waves of a        predetermined ultrasound frequency range;    -   providing an optimal positioning of the optical and acoustic        units with respect to each other and with respect to the region        of interest, said optimal positioning satisfying an operating        condition resulting in that the ultrasound waves of the        predetermined frequency range overlap with the illuminating        light within the region of interest, while substantially not        overlapping a region outside the region of interest, and in that        the detection assembly collects light scattered from the        overlapping region and from the region outside the region of        interest;    -   operating the optical and acoustic units, when in the optimal        positioning, and generating measured data indicative of        collected light including scattered light having ultrasound        tagged and untagged light portions, thereby enabling extraction        of a light response of the region of interest from all the other        light portions in the collected light.

According to yet another aspect of the invention, there is providedmethod for use in noninvasive monitoring at least one parameter of afetus-related region of interest, the method comprising:

-   -   providing an optical unit having an illumination assembly        configured to define at least one output port for the        illuminating light; and a light detection assembly configured to        define at least one light input port for collecting light, and        to generate measured data indicative of the collected light; and        providing an acoustic unit configured to generate acoustic waves        of a predetermined ultrasound frequency range;    -   providing an optimal positioning of the optical and acoustic        units with respect to each other and with respect to the        fetus-related region of interest, said optimal positioning        satisfying an operating condition resulting in that the        ultrasound waves of the predetermined frequency range overlap        with the illuminating light within the fetus-related region of        interest, while substantially not overlapping in a maternal        tissues region outside the fetus-related region of interest, and        in that the detection assembly collects light scattered from the        fetus-related region of interest and from the maternal tissues        region;    -   operating the optical and acoustic units, when in the optimal        positioning, and generating measured data indicative of        collected light including scattered light having ultrasound        tagged and untagged light portions, thereby enabling extraction        from the measured data a data portion indicative of a light        response of the fetus-related region of interest.

According to yet another aspect of the invention, there is provided amethod for operating a monitoring system configured for noninvasivemonitoring at least one parameter of a region of interest in a humanbody, which system comprises an optical unit and an acoustic unitconfigured to generate acoustic waves of a predetermined ultrasoundfrequency range, the method comprising:

-   -   operating the monitoring system to provide an optimal        positioning of the optical and acoustic units with respect to        each other and with respect to the region of interest to satisfy        an operating condition for measurements, said operating        condition resulting in that the ultrasound waves of the        predetermined frequency range overlap with illuminating light        generated by the optical unit within the region of interest,        while substantially not overlapping in a region outside the        region of interest, and in that a detection assembly of the        optical unit collects light scattered from the region of        interest and from the region outside the region of interest,        thereby obtaining measured data indicative of scattered light        having ultrasound tagged and untagged light portions, and        enabling extraction from said measured data a data portion        indicative of a light response of the region of interest.

The technique of the present invention may be used for noninvasivemonitoring of various parameters of human blood and tissue. Morespecifically, the present invention is useful for monitoring fetal bloodconditions and is therefore described below with respect to thisapplication.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, preferred embodiment will now be described, by way ofnon-limiting examples only, with reference to the accompanying drawings,in which:

FIG. 1A schematically illustrates a monitoring apparatus according toone embodiment of the invention for monitoring oxygen saturation or afetus or any other region of interest in a human or animal body;

FIG. 1B exemplifies an operating method of the apparatus of FIG. 1A;

FIG. 2 schematically illustrates a monitoring apparatus, according toanother embodiment of the present invention;

FIG. 3A schematically illustrates a monitoring apparatus according tothe invention configured to be capable of monitoring the fetal andmaternal oxygen saturation;

FIG. 3B illustrates a flow diagram of the main steps in a method of theinvention using the apparatus of FIG. 3A;

FIG. 3C shows a flow diagram of a specific example of the method of FIG.3B;

FIG. 3D schematically illustrates yet another example of a monitoringsystem of the present invention configured for monitoring the amnioticfluid condition;

FIG. 4 schematically illustrates a monitoring apparatus, according toyet another embodiment of the present invention;

FIG. 5 schematically illustrates a monitoring apparatus, according toyet another embodiment of the present invention;

FIGS. 6A and 6B show bottom and side views, respectively, of a flexibleprobe according to one embodiment of the invention;

FIGS. 7A and 7B show bottom and side views, respectively, of a flexibleprobe according to another embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIG. 1A, there is schematically illustrated a monitoringapparatus, generally designated 100, constructed and operated as a fetaloxygen saturation monitor according to the invention. It should,however, be understood that the apparatus configuration is suitable formeasuring various other parameters of a fetus 2 (such as theconcentration of an analyte in the fetal blood, or the perfusion of ananalyte/metabolite in fetal or maternal tissues). It should beunderstood that the apparatus of the present invention may be used formonitoring blood or tissue parameters of a human being.

The apparatus 100 includes such main constructional parts as ameasurement unit formed by an optical unit 101 including an illuminationassembly 101A and a light detection assembly 101B; and an acoustic unitincluding a transducer arrangement 110. In the present example of FIG.1A, the detection assembly includes a single detection unit. In thisconnection, it should be noted that the term “single detection unit” notnecessarily signifies a single detector, but may refer to an array ofdetectors, provided they are associated with the same location withrespect to the illuminated region.

The optical and acoustic units are connectable to a control unit 120.The control unit 120 is typically a computer system including inter aliaa power supply, a control panel with input/output functions, a memoryutility, a data presentation utility (e.g., display), a data acquisitionassembly, and a data processing and analyzing utility (e.g. CPU). Thecontrol unit 120 includes a signal generator (e.g. function generator)120A to control the operation of the transducer arrangement 110, and anappropriate utility 120B for operating the optical unit 101. The CPU ispreprogrammed for receiving measured data coming from the detectionassembly 101B and processing this data to determine the desiredparameter, e.g., oxygen saturation of the fetus.

In the present example, the optical unit 101 is configured as a portableprobe including a support structure 103 carrying at least a part of theillumination assembly 101A and at least a part of the detection assembly101B. The illumination assembly 101A is preferably configured forgenerating light of at least two different wavelengths. To this end, theillumination assembly may include at least two light emitters (e.g.,laser diodes), one emitting narrow bandwidth photons of a wavelengthwithin the range of 605 nm to 805 nm and the other emitting photons of awavelength within the range of 800 nm to 1300 nm. The illuminationassembly 101A may for example be preprogrammed to produce the differentwavelength components at different times, or simultaneously producewavelength components with different frequency- and/or phase-modulation.Accordingly, the control unit 120 is preprogrammed to identify, in asignal generated by the detection assembly 101B, the correspondingwavelength of the irradiating light, using time, phase or frequencyanalysis.

The illumination assembly 101A may include light emitter(s) carried bythe support structure 103 and communicating with the control unit 120via an output port 121 of the light emitter(s) using wires 106 orwireless signal transmission. Alternatively, the light emitter(s) may belocated outside the support structure 103 (e.g., within the control unit120) and a light guiding assembly 106 (e.g., optical fibers) is used forguiding light to the output port 121 located on the support structure103.

The detection assembly 101B includes one or more light detectors. Thismay be a photomultiplier tube, or preferably an image pixel array, e.g.,CCD or an array of photodiodes. It should be noted that, for thepurposes of the present invention, an input port 122 of the detectionassembly 101B is larger than that used for imaging by means of diffuselight. In diffuse light imaging, localization is achieved by small inputports, otherwise light from a large volume is collected. According tothe invention, light collection from a large volume is desired, sincelocalization is achieved by the ultrasound tagging. Hence, the inputport 122 of the detection assembly 101B is optimized to collect lightfrom a substantially large volume of tissue and/or blood, for example byusing large area detectors or CCD cameras or an array of detectorscomprising a single input port.

As indicated above, the detection assembly 101B may include two separatedetectors or an array of detectors. Each detector may be coupled to abandpass filter configured for transmitting light of a corresponding oneof the wavelengths produced by the illumination assembly 101A. Thebandpass filters may include high-pass, low-pass and bandpass opticalfilters. Alternatively narrow bandwidth detectors can be used.

It should be understood that the detector(s) may be accommodated outsidethe support structure (probe) 103, e.g., may be located within thecontrol unit 120, and returned light (light response) may be guided fromthe input port 122 of the detection assembly via light guiding means 105(e.g., optical fibers). It should also be understood that the connectors105 and 106 may be electric wires connecting the control unit 120 to theillumination assembly and detection assembly located on the probe 103,or the connection may be wireless.

Thus, generally, the terms “illumination assembly” and “detectionassembly” or “detection unit” as carried by a support structure which isbrought in contact with a human body, are constituted by at least lighttransmitting and receiving ports. Probes (kits) of the present inventionincluding light transmitting and receiving ports and preferably alsoacoustic ports, will be described further below with reference to FIGS.6A-6B and 7A-7B.

The control unit 120 (its signal generator 120A and CPU) is connected tothe transducer arrangement 110 using cables 107 and/or using wirelessmeans.

An example of a monitoring method of the present invention, using theapparatus 100, will now be described with reference to FIG. 1B.

Step 1: Prior to performing the actual measurements, an optimalpositioning of the assemblies of the optical unit and of the acousticunit with respect to a region of interest (fetus) is provided to satisfyan operating condition for measurements. The operating condition is suchthat both light (at least a portion of the illuminating light) and theacoustic radiation irradiate the same region (volume) simultaneously,while substantially not overlapping in outside regions (maternal tissues11); and that the detection assembly detects light scattered from boththe region of interest and regions outside thereof. Preferably, theregion where the ultrasound and light overlap is the region of interest(fetus 2), but generally a region outside the region of interest may beselected to be overlapping region. Generally speaking, the positioningof the optical unit and transducer arrangement with respect to the fetus2 is such as to enable distinguishing between scattered photonscollected from the maternal tissues 11 and from the fetus 2 usingultrasound tagging of light.

This pre-positioning utilizes an ultrasound imaging of the region ofinterest. To this end, an imaging system of any known suitableconfiguration may be used, which may utilize the same transducerarrangement 110 used for the measurement process or another ultrasoundtransducer(s). Ultrasound images of the maternal tissues 11 (e.g.abdomen, uterus) and of the fetus 2 are acquired and analyzed by thecontrol unit 120 (which in this case is installed with a suitable imageprocessing utility) or another appropriately preprogrammed computersystem, to determine the optimal positioning of the optical unit 101(namely the illumination assembly 101A and the detection assembly 101B)relative to the fetus and relative to the acoustic unit 110.

It is important to note that according to the invention, ultrasoundtagging is utilized for the purposes of “tagging” a light response froma selected region of interest (fetus), thus enabling processing ofdetected tagged and untagged light portions to identify the lightresponse of the selected region of interest. This is contrary to theknown techniques where ultrasound tagging is used for imaging purposesto enable two and three-dimensional imaging.

The illumination assembly 101A is preferably placed at the shortestdistance to the fetus 2, preferably to the fetal head. It should beunderstood that other organs or tissues of fetus 2 may be chosen formeasurements as well. Preferably, the illumination assembly 101A isplaced such that a light path between the illumination assembly 101A andthe fetus 2 is that suffering the least attenuation at the wavelengthschosen for measurements, as compared to the other paths. The distancebetween the illumination assembly 101A and the detection unit 101B ispreferably determined to be at least equal to and preferably larger thanthe distance between the illumination assembly 101A and the head of thefetus 2.

Preferably, the support structure 103 is configured to define variouspositions for attaching the detection unit 101B and/or the illuminationassembly 101A to be at the correct distance between them. For example,these positions may be determined by using a sliding bar (not shown)that is attached to the light detection unit 101B and can be secured tothe support structure 103 using a small screw or a latch. Alternatively,a plurality of light output ports and/or plurality of light input portsare provided on the support structure 103 and the control unit 120operates to select the appropriate light source(s) and detector(s)(light output port and light input port) for measurements. Thisselection is based on the signals generated by each detector and on thegeometry of the maternal tissues and the position of the fetus.

Additionally, the illumination assembly 101A and the detection unit 101Bare placed such that the light output port 121 of the illuminationassembly and the light input port 122 of the detection assembly are inclose contact with an outer skin 10 of the maternal abdomen. Optionally,an index matching oil or adhesive is used to reduce reflection of lightfrom the outer skin 10. The adhesive may be used to secure the apparatus100 to a specific location on the maternal abdomen. Alternatively, oradditionally, a belt can be used to prevent movement of the apparatus100.

Once the position of the illumination assembly 101A and the detectionassembly 101B is fixed, the ultrasound transducer arrangement 110 ispositioned such that acoustic waves 150 generated by the transducerarrangement 110 are coupled into the maternal abdomen, propagate throughuterus and amniotic fluid, and reach the fetus 2. For example, in thecase the illumination assembly 101A and detection assembly 101B areappropriately placed to illuminate and collect light scattered by thefetus head, the transducer 110is placed such that the acoustic waves 150propagate through the same region of the head from which scatteredphotons 155 are detected by the detection assembly 101B. The transducer110 may be fixed to an appropriate location using an ultrasoundtransmitting adhesive or using gel for acoustic coupling, and optionallya belt for fixing the transducer to one location. Alternatively, theultrasound transducer arrangement 110 is configured as a phased arraytransducer producing a focused beam that is being scanned over a regionof skin 10 overlaying the maternal tissues 11.

Step 2: Having optimally positioned the illumination assembly 101A,detection unit 101B and ultrasound transducer arrangement 110,measurements are taken by appropriately operating the apparatus 100. Thecontrol unit 120 actuates the illumination assembly 101A to generatephotons 155 of at least two wavelengths. The photons 155 propagatethrough maternal tissues, through the uterine wall, and reach the fetus2. A portion of photons 155 is absorbed by hemoglobin in the fetusblood, and a portion of photons 155 is scattered by tissues and cells ofthe fetus 2 and of the mother. A portion of the scattered photons 155propagates through the maternal tissues 11 and reaches the detectionassembly 101B. The latter collects at least a part of this portion ofthe scattered photons 155 and generates measured data indicativethereof, i.e., an electric signal in response to the number of photonsthat are collected at the input port 122 of the detection unit at aspecific point in time for each irradiating wavelength generated by theillumination assembly 101A.

It should be noted that, in the case the detection assembly 101B isspaced from the illumination assembly 101A a distance equal to or largerthan twice the minimal distance between the fetus 2 and the illuminationassembly 101A, the detection unit 101B collects both back and forwardscattered photons. In the case the illumination assembly 101A includes alaser with a coherence length larger than the optical path of scatteredphotons in the tissue, an interference pattern resulting in a speckleimage is generated on the input port 122 of the detection assembly. Inorder to detect and analyze the speckle image, the detection assembly101B may include an array of detectors with an individual sizecomparable to that of individual speckle. The illumination assembly 101Amay be configured and operable to produce a continuous stream of photons155 (CW), or a time modulated stream (at a certain frequency W), or atrain of pulses.

In the present example of FIG. 1A, a portion of detected photonsscattered by the fetus 2 are tagged by ultrasound waves, while detectedphotons scattered by the maternal tissues 11 are untagged. As photons155 illuminate the fetus 2, the transducer 110 generates acoustic waves150 that propagate through maternal tissues to irradiate the same volumeof the fetus 2 from which scattered photons 155 are detected by thedetection assembly 101B. The interaction of acoustic waves 150 withphotons 155 results in that the frequency of photons 155 is shifted bythe frequency of acoustic waves 150 (acousto-optic effect). Thesefrequency-shifted or frequency-modulated photons are thus “tagged” andcan be identified. The detection assembly 101B detects both thefrequency shifted photons (“tagged photons”) and the photons at theoriginal frequency (“untagged photons”) at both wavelengths. Thedetection assembly 101B generates measured data (electric signals) inresponse to both the tagged and untagged photons.

Step 3: The control unit 120 processes the measured data using anappropriate algorithm according to the type of detection used. Forexample: in the case of a single (large area) detector, heterodynedetection (e.g., as described by [Lev A. and B. G. Sfez Optics Letters(2002) 27 (7) 473-475]) is used to separate data indicative of thesignal of the tagged photons; when a CCD camera is used and a fullspeckle image is detected, the technique described by [Leveque-Fort etal. in Optics Communication 196 127-131 (2001)] is used to determine theoptical signal of photons scattered from the particular volume which istagged by ultrasound waves.

Using the above, or other suitable, techniques, it is possible todetermine the effective attenuation of photons 155 as they propagatethrough the fetus 2. To this end, ultrasound radiation may be appliedsuch that acoustic waves 150 propagate through different depths of thefetal tissues (e.g., by displacing the transducer arrangement withrespect to the body or by using a phase array transducer). Accordingly,the absorption coefficient and the reduced scattering coefficient can beisolated in the two wavelengths chosen for illumination. For example,using a similar equation to equation 4 of Lev et al. referenced above:

$x = \frac{\gamma_{6}^{O} - {\frac{\mu_{{eff},6}}{\mu_{{eff},8}}\gamma_{8}^{O}}}{\left\lbrack {\left( {\gamma_{8}^{H} - \gamma_{8}^{O}} \right) - {\frac{\mu_{{eff},6}}{\mu_{{eff},8}}\left( {\gamma_{6}^{H} - \gamma_{6}^{O}} \right)}} \right\rbrack}$it is possible to determine the oxygen saturation level of the fetus.Here, x is the fraction of deoxyhemoglobin, γ are the molar extinctioncoefficients of oxyhemoglobin(O) and deoxyhemoglobin (H) at bothwavelengths (in the referenced paper, 6 stands for 690 nm and 8 for 820nm) and μ_(eff,6) and μ_(eff,8) are the measured attenuationcoefficients at 690 and 820 nm, respectively.

The ultrasound transducer 110 is kept at a specific location, which isoptimal for propagating acoustic waves through the same volume of thefetal body (such as the head) from which scattered photons 155 aredetected by the detection assembly 101B. The beam size of transducer 110is such that the cross section volume between photons 155 and acousticwaves 150 is as large as possible, whether focused or not, forincreasing the signal to noise ratio (SNR) of the detection system,without compromising the sensitivity to detect only the fetal oxygensaturation and not the maternal one.

As indicated above, the present invention utilizes ultrasound taggingfor the purposes of distinguishing between light responses of theregions of the fetus 2 and the region of maternal tissues 11.Preferably, the frequency of acoustic waves generated by the transducerarrangement 110 is in the range of 50 kHz-8 MHz, and morepreferably—lower than 1 MHz. This frequency range provides a better SNRfor ultrasound tagged light, as it increases the fraction of photonsthat are tagged, but results in a lower focusing resolution. This is incontrast to imaging modalities known in the art, where it is desired toimprove the imaging resolution and thus higher frequencies and minimalcross section are conventionally chosen. In addition, the detectionassembly 101B collects forward and back scattered photons according tothe preferred geometry of FOSM 100. Therefore, a number of photonscollected by the detection assembly 101B is higher than in cases ofreflection based imaging disclosed in the above references, thusenabling an improved SNR. Hence, the invention enables using safer lightenergies for illumination. It should be understood that such aconfiguration, although rendering high resolution imaging morecomplicated than the case where primarily back scattered photons aredetected, is highly suitable for fetal oximetry.

The control unit 120 analyzes both back and forward scattered taggedphotons to determine the optical attenuation of light propagatingthrough the fetal head. Consequently, the control unit 120 needs notperform high resolution imaging of the fetus, but rather just analyzethe collected photons 155 scattered by a large volume of the fetaltissues.

Step 4: The control unit 120 processes that portion of the measureddata, which is associated with tagged photons scattered from the fetus(identified as described above), to determine the desired parameter ofthe fetus—oxygen saturation in the present example. Two modalities canoptionally be used to determine the oxygen saturation level of a fetusintrautero, one being based on measuring the average oxygen saturationlevel (known as oximetry) and the other being based on measuring theoxygen saturation level correlated with changes in the blood volumeduring the cardiac cycle (known as pulse oximetry).

Oxygen saturation S is a ratio between the concentration of oxygenatedhemoglobin [HbO] and the total concentration of hemoglobin [HbT] inblood:S=[HbO]/[HbT](*100%)   [1][HbT]=[HbO]+[Hb]  [2]wherein [Hb] is the concentration of deoxygenated hemoglobin.

The saturation S can be extracted from the attenuation coefficientmeasured for at least two wavelengths λ₁ and λ₂, where the molarabsorption and scattering coefficients for Hb and HbO at each wavelengthare known in the literature. It should be noted that more than twowavelengths can be used, to improve sensitivity of the measurement.

As the arteries expand, a blood volume [HbT] is increased by [ΔHbT],therefore absorption changes periodically. The optical attenuation at λ₁and λ₂ is measured at predetermined points (for example, the maxima andminima of a power spectrum of the tagged signal or the processed taggedsignal, as defined below) generated by the detection assembly 101Bduring a cardiac cycle. As indicated above, in the present exampletagged signal is that associated with the fetus. The saturation S can becalculated from differences in attenuation of light (ΔOD) at eachwavelength between maxima and minima.ΔOD ^(λ)=(μ_(HbO) ^(λ) [HbO]+μ _(Hb) ^(λ) [Hb])d=(μ_(HbO) ^(λ) S+μ _(Hb)^(λ)(1−S)) [HbT]d   [3]wherein μ_(HbO) ^(λ), μ_(Hb) ^(λ) are the molar attenuation coefficientof oxygenated and deoxygenated hemoglobin respectively, at wavelengthλ(λ=λ₁,λ₂) and d is the distance from the source to the target tissue(fetal or maternal).

Defining the ratio R between ΔOD^(λ) at each wavelength λ₁ and λ₂:

$\begin{matrix}{R = {\frac{\Delta\;{OD}^{\;{\lambda\; 1}}}{\Delta\;{OD}^{\;{\lambda\; 2}}} = \frac{\left\lbrack {{\mu_{HbO}^{\lambda\; 1}S} + {\mu_{Hb}^{\lambda\; 1}\left( {1 - S} \right)}} \right\rbrack}{\left\lbrack {{\mu_{HbO}^{\lambda\; 2}S} + {\mu_{Hb}^{\lambda\; 2}\left( {1 - S} \right)}} \right\rbrack}}} & \lbrack 4\rbrack\end{matrix}$saturation S is extracted from equation [4] when ΔOD^(λ1) and ΔOD^(λ2)are measured and the molar attenuation coefficients are known.

According to an embodiment of the present invention, the control unit120 analyzes signals generated by the detection assembly 101B inresponse to each wavelength λ₁, λ₂ generated by the illuminationassembly 101A. The signals corresponding to tagged photons 155 areselected by the detection assembly 101B using heterodyne detection, orby the control unit 120 using frequency analysis and/or speckle imaging.These signals are termed “tagged signals”. The time dependent amplitudeand/or phase of the tagged signals for each wavelength λ₁, λ₂ is storedin the memory of the control unit 120, over a specified period of timeof at least one fetal heart cycle. To determine the oxygen saturationlevel of the fetus, the control unit 120 determines the changes inattenuation of tagged signals at each wavelength.

Considering the determination of oxygen saturation of fetus 2 based onoximetry, the time averaged signals generated by the detection assembly101B in response to the tagged photons 155 of at least two illuminatingwavelengths reaching the input port 122, are used to determine theoxygen saturation level. Time averaging can be performed over longertime scales than the duration of a fetal heart cycle.

Considering pulse oxymetry used for determining oxygen saturation of afetus, the temporal changes (due to the fetal cardiac cycle) in theblood volume of the fetus are monitored by the control unit 120 bymonitoring the low-frequency changes (1-2.5 Hz) in the signals generatedby the detection assembly 101B in response to the tagged photons 155 ofat least two illuminating wavelengths reaching the input port 122 of thedetection assembly. Since the ultrasound frequency is orders ofmagnitude higher than the fetal heart rate, it is possible to averagethe signals responsive to tagged photons over a fraction of the fetalheart cycle to improve the SNR of the measurement. Using methods ofpulse oximetry, both the oxygen saturation and the pulse rate aredetermined simultaneously.

The control unit 120 displays the determined fetal oxygen saturationlevel, along with fetal heart rate, as a function of time. Fetal heartrate is determined by low-frequency analysis of the tagged signals. Thecontrol unit 120 optionally alerts using a suitable indication utility(e.g. sound and/or light signal), when oxygen saturation level dropsbelow a certain threshold (for example 30% or 40%), or when fetal heartrate changes abnormally.

Preferably, monitoring apparatus 100 provides for calibrating formovements of fetus 2 during the measurement. To this end, the controlunit 120 operates to determine the position of fetal head relative tothe apparatus 100. This is carried out either periodically, or upondetection of signals not corresponding to a normal heart rate or oxygensaturation level. The control unit 120 sends a control signal to thetransducer arrangement 110 initiating an ultrasound echo measurement. Inan echo measurement, the transducer arrangement 110 transmits acousticwaves 150 into maternal tissues, and collects acoustic waves 150reflected by fetal and maternal tissues. The reflected signals areanalyzed by the control unit 120 (using any conventional ultrasoundimaging technique) to determine a position of the fetal head. If asubstantial movement is detected, the control unit 120 sends a signal tothe transducer arrangement 110 to optionally change a direction ofacoustic waves 150 in a new direction corresponding to a new position ofthe fetus 2. Additionally or alternatively, the control unit 120 alertsthe operator of apparatus 100 to readjust the position of the apparatusaccordingly.

Although the above description refers to a single fetus, it should beunderstood that the technique of the present invention can easily beadapted for monitoring several fetuses intrautero. The location of eachfetus is determined using an ultrasound imaging system, and differentmonitoring apparatuses (i.e., optical and acoustic units) or anintegrated multi-fetuses apparatus are used. All the monitoringapparatuses can be hooked to the common control system that controlseach apparatus separately, and processes the signals using the same ordifferent processing utilities. A display shows the oxygen saturationlevel of each fetus separately along with its heart rate and otherparameters.

The present invention also provides for advantageously utilizing theprinciples of ultrasound tagging of light in pulse oximetry formonitoring oxygen saturation in a localized region of interest in ahuman or animal body (without a fetus). Turning back to FIG. 1A, theoptical unit 101 is configured as a pulse oximeter, namely includes anillumination assembly 101A configured to generate light of at least twodifferent wavelengths and a light detector 101B; and is used incombination with the transducer arrangement to significantly improve thepulse oximetric measurements. The monitoring apparatus 100 may beconfigured to operate in a transmission mode (light transmission baseddetection), such as the conventional pulse oximeter placed on a fingeror earlobe. In this case, the support structure 103 is located such thatthe illumination assembly 101A is co-linear with the detection assembly101B: the illumination assembly 101A is placed at one side of the tissueand the detection assembly 101B is placed at the opposite side of thetissue, therefore ballistic and scattered light emitted fromillumination assembly 101A are detected by detection assembly 101B. Thetransducer arrangement 110 is placed such that acoustic waves overlapwith an illuminated region in the region of interest from whichscattered light reaches the detection assembly 101B, which is preferablythe region encompassing a blood vessel (e.g. an artery) or a collectionof arterial vessels. In other applications, requiring reflection baseddetection from a region of interest (“reflection mode”), the apparatus100 is located as described for the fetus-related application, where theregion of interest preferably encompasses a blood vessel (e.g. anartery) or a collection of arterial vessels. Such an arrangement issuperior to conventional pulse oximeter as it is not affected byincoherent ambient light, and more importantly is less affected bymotion of the tissue relative to illumination and detection assemblies,as long as the region of interest is kept illuminated and the acousticwaves propagate through it.

It should be understood that using the ultrasound tagging of light inthe pulse oximetry based measurements significantly improves themeasurements, since the measured power spectrum of an ultrasound-taggedlight signal is practically insensitive to movements of the region ofinterest under measurements, which is the common problem of the typicalpure pulse oximetry measurements.

FIG. 2 exemplifies another configuration of a fetal oxygen saturationmonitor, generally designated 200, of the present invention. Tofacilitate understanding, the same reference numbers are used foridentifying components that are common in all the examples of theinvention. In the apparatus 200, an illumination assembly 101A includesa light source 201A mounted within a control unit 120 and an opticalfiber 201B guiding light from the light source to the region of interest(fetus). The optical fiber 201B is inserted into the vaginal track ofthe pregnant woman (using suitable means, for example a flexible supportstructure which is not specifically shown). The optical fiber 201B ispositioned such that it is in close contact with the cervix or toamniotic membranes prior to rupture. Optionally, following membranerupture optical fiber 201B is attached to the presenting part of thefetal head with the aid of a support structure. A light detectionassembly 101B is placed on the maternal abdomen, such that it collectsphotons scattered by the fetal blood. The detection assembly 101B isconnected to a suitable utility of the control unit 120 via wires (asshown in the figure) or wireless. An ultrasound transducer arrangement110 is also placed transabdominally such that acoustic waves 150 canpropagate through the part of the head of a fetal 2 being closest to theoptical fiber 201B and detection assembly 101B. In some cases, it may beadvantageous to introduce the transducer arrangement 110 also throughthe vaginal track.

Reference is made to FIG. 3A exemplifying a preferred embodiment of amonitoring apparatus 300 according to the invention. The apparatus 300is configured generally similar to the above-described apparatus 100,namely includes an acoustic transducer arrangement 110, and an opticalunit 101 having a probe 103 carrying at least a part of an illuminationassembly 101A and at least a part of a detection assembly. Here, thedetection assembly is formed by two detection units 101B and 101Cassociated with different locations with respect to the illuminatedregion defined by a location of the illumination assembly 101A. Theadditional detection unit 101C is also attached to the support structure(probe) 103 and is connected to a control unit 120 via electrical cable(not shown) or wireless means.

One of the detection units—detection 101C in the present example, islocated in the proximity of the illumination assembly 101A, and theother detection unit 101B is located at a larger distance from theillumination assembly. In the present example, the detection unit 101Cis located between the illumination assembly 101A and the detection unit101B. Generally, the arrangement of the illumination assembly anddetection units is such that one of the detection units (detection unit101C) is located close to the illumination assembly to therefore detectphotons 165 scattered from regions outside the fetus 2 (i.e., lightreaches the detector 101C prior to reaching the fetus); and the otherdetector 101B) is more distant from the illumination assembly and thusdetects photons 155 scattered from the fetus and propagating through thematernal tissues region and being thereby affected by the maternaltissues.

The transducer arrangement 110 is aligned and/or scanned, such that ittransmits acoustic waves 150 to the volume within the illuminated regionof the fetus from which photons 155 are detected by the detection unit101B, and substantially does not irradiate the maternal tissue regionfrom which photons 165 are collected by the detection unit 101C.

Signals (measured data) generated by the detection unit 101C may be usedby the control unit 120 to determine the maternal oxygen saturationlevel and heart rate simultaneously, which may thus be displayed.Generally, the use of the additional detection unit 101C located closeto the illumination assembly 101A assists in separating a light responseof the fetus region 2 from that of the maternal tissues' region 11,since the detection unit 101C so-positioned will detect scatteringeffect of light that traveled through the maternal tissues and did notreach the fetus, and which is thus indicative of the maternal regionresponse only. The other detection unit 101B practically detects photons155 including the tagged response of the fetus and the tagged responseof the maternal tissues.

It should be understood that generally the detection unit detects thetagged light response of the fetus affected by the maternal tissues.Hence, the expression “tagged response of the maternal tissues” meansphotons tagged (by ultrasound) inside the volume of the fetus beingscattered by maternal tissue.

Both the tagged and untagged responses of the maternal tissues' regionare identically frequency modulated by the mother's heart rate. Hence,the first measured data from the detection unit 101C, which is mainlyindicative of the untagged light response of the maternal tissues, canbe used to analyze the second measured data from the detection unit 101Bto separate a signal indicative of a light response of the fetus fromthat of the maternal tissues.

FIG. 3B illustrates a flow chart of the main operational steps of amethod of the invention utilizing the monitoring system 300.

Step 1: First, optimal positioning of the illumination assembly,detection assembly and acoustic transducer arrangement is provided asdescribed above. This positioning ensures that acoustic waves interactwith the region of interest (fetus volume) from which photons 155 aredetected at the detector 101C and substantially do not interact with theregion outside the region of interest (maternal tissues) from whichphotons 165 are detected by the detector 101C.

Step 2: Actual measurements are performed when at the optimal positionsof the illumination, detection and acoustic assemblies. Measured dataincludes: (1) a first data portion generated by the detection unit 101Cand indicative of the untagged photons coming from the maternal tissues;and (2) a second data portion generated by the detection unit 101B andindicative of the photons including tagged and untagged photons comingfrom the fetus, and untagged photons coming from the maternal tissues.

Step 3: The measured data is processed to filter out, the contributionof tagged and untagged photons scattered by regions outside the regionof interest, to the measured signal, wherein this contribution isidentified as that having frequency modulation by the mother's heartrate, as previously identified from the data portion (1). Hence, theso-separated light response of the fetus can be processed to determinethe desired parameter of the fetus. The control unit 120 may use signalsgenerated by the detection units 101B and 101C to determine fetal andoptionally maternal oxygen saturation levels.

More specifically, the apparatus 300 operates as follows: Theillumination assembly 101A simultaneously generates photons of twodifferent wavelengths (generally, at least two wavelengths). Photonsdenoted 155 are photons scattered from maternal and fetal tissues andreaching an input port 122 of the detection unit 101B, i.e., photonsscattered from a tagged volume of tissue, that is intermittently orcontinuously radiated by acoustic waves 150 generated by transducer 110.

The transducer arrangement 110 may, for example, be operated to generatea burst of acoustic waves, with a delay of at least t_(on) between theend of one burst and the onset of another burst. Time t₀ is the time ittakes the acoustic burst to reach the target fetal tissues (e.g. head).The duration of the burst Δt₀ is determined such that at time t_(f),bounded by a condition t₀≦t_(f)≦(t₀+Δt₀), the acoustic pulse propagatesprimarily through target fetal tissues (i.e., through a volume ΔV offetal tissues). Therefore, during this time t_(f) the acoustic burstreaches the target fetal tissues, and acoustic waves are hardlypropagating through maternal tissues. A portion of photons 155propagating through the same volume of fetal tissues during time t_(f)is tagged. Whereas, photons 165 are those propagating only throughmaternal tissues at the same time t_(f) and are therefore untagged(since they did not interact with the ultrasound irradiated region).

The detection unit 101C is placed at a distance Q from the illuminationassembly 101A, such that its input port collects primarily photons 165that are not scattered from the tagged volume. The detection unit 101Cis optionally moved until it does not collect tagged photons, and isthen fixed in the appropriate position. It should be noted that,alternatively, the detection units 101B and 101C are fixed in place, anda position of the ultrasound transducer arrangement 110 is adjusted tobe such that the tagged photons 155, scattered from fetal tissues,primarily reach the detection unit 101B and not the detection unit 101C.

FIG. 3C more specifically exemplifies the data processing procedure forprocessing measured data from the apparatus 300. The detection unit 101Breceives photons 155 including tagged and untagged photons scattered bythe uterus and tagged photons scattered by the fetus, while thedetection unit 101C receives primarily only untagged photons 165scattered by the maternal tissues. A signal that is generated by thedetection assembly 101B in response to collected photons 155 is referredto as “signal A”. A signal generated by the detection unit 101C inresponse to photons 165 is referred to as “signal B”.

According to this example, two models are used to describe thepropagation of light in a multi layer tissue system. Such models aredescribed for example by Keinle et al. in Physics in Medicine andBiology 44: 2689-2702 (1999). One model (Model A) includes theparameters representing some of the tissues through which photons 165propagate from the illumination assembly 101A through a medium untilthey reach the detection unit 101C, and the other model (Model B)includes the parameters representing some of the tissues in the mediumthrough which tagged photons 155 propagate until they reach thedetection unit 101B. The models include known parameters, such as themolar absorption and scattering coefficients of blood cells, and ofoxygenated hemoglobin and deoxygenated hemoglobin at each of thewavelengths of illuminating photons. In addition, the models may includethe thickness of the layers (maternal and fetal), presence and volume ofamniotic fluid in the light path and other parameters that are measuredduring the operation of apparatus 300 (as described above with referenceto apparatus 100 of FIG. 1). Some tissue parameters in the model may beaveraged or other manipulations of the known or measured parameters ofthe real tissues in models A and B may be carried out.

Given a certain source amplitude, and the known separation between theillumination assembly 101A and the detection unit 101C, model A is usedto calculate the expected time dependent photon flux, or light intensityat the input port of the detection unit 101C. The expected timedependent photon flux or light intensity is used to calculate theexpected signal (termed “signal C”) that can be generated by thedetection unit 101C in response to such a photon flux. Signal C actuallypresents theoretical data for untagged photons at the location ofdetection unit 101C, while signal B presents real measured data foruntagged photons collected by the detection unit 101C. The parameters ofmodel A are adjusted such that signal C is made equal to or closelyresembles signal B (best fitting). Signal processing techniques based onoptimization algorithms, such as neural network, can be used tooptimally determine the parameters of model A. The parameters are usedto calculate the optical properties of some of the tissues through whichphotons 165 propagate.

Additionally or alternatively, certain parameters of models A and B(such as thicknesses of maternal tissues, in particular uterine wall,and/or tensions of muscles) may be unknown, and be determined duringoperation. During contractions, the thickness of the uterine wall andthe tension of the muscles change. Controller 120 determines thethickness of the uterine wall as a function of time by optimizingprimarily this parameter of model A. Once determined, these parametersare used to determine contractions' duration and amplitude.Alternatively, tissue velocity measurements are performed by ultrasoundassembly 110, using techniques known in the art for echocardiography.Transducer arrangement 110 emits acoustic pulses (not shown) that arereflected back by uterine muscles. The reflected pulses are Dopplershifted with respect to the emitted acoustic pulses. Controller 120analyzes the reflected signals to determine the thickness and velocityof the muscles. During contractions the thickness and velocity change,therefore controller 120 monitors these changes as a function of time.Consequently, controller 120 displays the amplitude and duration of thecontractions. The apparatus 300 thus provides information needed tomonitor the progression of labor (contractions' duration and amplitude)in addition to fetal well being (heart rate and oxygen saturation).

In addition, signal B is optionally used to extract maternal oxygensaturation level, by using the time dependent amplitudes of the signalsgenerated by the detection unit 101C in response to photons 165 of atleast two wavelengths.

It may generally be assumed that the optical properties of tissuesoutside the region of interest (outside fetus) through which bothphotons 155 and 165 propagate are similar (for example maternalabdominal tissues). Alternatively, it may be assumed that by determiningthe parameters and optical properties of the tissues through whichphotons 165 propagate, one can deduce, within a reasonable error, theoptical properties of corresponding tissues (e.g., other areas ofmaternal abdominal tissues) through which photons 155 propagate. Theparameters calibrated by signal B and the optical properties of thetissues through which photons 165 propagate are then used to calibratemodel B that describes the propagation of photons 155 through maternaland fetal tissues.

The time dependent amplitude of signal A at all wavelengths of photons155 is processed by the control unit 120 using techniques known in theart, such as digital Fourier transformations and analog or digitalfiltering, to extract, from the entire signal A, a signal portioncorresponding to the tagged photons 155. This signal portion is termed“tagged signal A”. Tagged signal A is that modulated at the ultrasoundfrequency generated by the transducer arrangement 110. The amplitude ofthe power spectra of the tagged signal A at the ultrasound frequency (orrelated to the ultrasound frequency), the modulation width of its powerspectra or other features of tagged signal A, such as its phase, aretermed together as “processed tagged signal A” This processed taggedsignal A is actually indicative of both the maternal tissues responseand the fetus response tagged by ultrasound. In addition, the signal Acontains information which is not modulated at the ultrasound frequency,termed “untagged signal A”.

According to this specific embodiment, untagged signal A may also beused in the data processing and analyzing procedure, for example todetermine some of unknown parameters of model B and further optimizethis model. For example, untagged signal A may contain signals which aremodulated by maternal cardiac cycle, and have a modulation frequency of0.5-2 Hz corresponding to maternal heart rate F_(m). Signal B is alsomodulated at the same frequency, as photons 165 propagate throughmaternal tissues containing the same pulsating blood. Consequently,untagged signal A and signal B may be used to calibrate model B relativeto model A, where differences and similarities between untagged signal Aand signal B are used to optimize the parameters of model B.

In addition, tagged signal A and/or processed tagged signal A are alsomodulated at maternal heart rate, as tagged photons 155 pass throughmaternal tissues before and after they pass through the tagged volume.Consequently, tagged signal A and/or processed tagged signal A modulatedat this low frequency may be used in conjunction with untagged signal Aand/or signal B to extract the portion of tagged signal A that isaffected by absorption by fetal blood. This portion calculated for allwavelengths of photons 155, is used to extract the fetal oxygensaturation level.

According to another embodiment of the invention, only tagged signal Aand untagged signal A at all the wavelengths of photons 155 are used toextract fetal oxygen saturation levels. According to yet anotherembodiment, tagged signal A and/or processed tagged signal A are used todetermine fetal oxygen saturation at all fetal heart rates F_(f), whereF_(f)≠F_(m) (or more precisely F_(f)>F_(m)+BW, where BW is the bandwidthof the detection system, as fetal heart rate is usually faster thanmaternal heart rate). First, tagged signal A is extracted (separated) bythe control unit 120 as described above. Then, the modulation amplitudesof tagged signal A and processed tagged signal A at F_(f) and F_(m) aredetermined. Tagged photons 155 are modulated at F_(f), however amodulation at F_(m) may also exist, as tagged photons 155 also propagatethrough maternal tissues. When this modulation is small, itscontribution at higher harmonics (i.e., 2F_(m), 3F_(m)) is negligible.The amplitudes of tagged signal A, processed tagged signal A anduntagged signal A modulated at frequency F_(m) are optionally used todetermine certain tissue parameters in model B. Using these parameters,tagged signal A is calibrated to correspond primarily to fetalcontributions. Fetal oxygen saturation is extracted from features (suchas the modulation amplitude, the bandwidth of the modulation,autocorrelation etc.) of the calibrated tagged signal A and/or processedtagged signal A modulated at F_(f) at all wavelengths of photons 155.

In some cases where the modulation of tagged signal A at F_(f) in therange of 2F_(m)−BW<F_(f)<2F_(m)+BW can not be neglected, signal B anduntagged signal A are used to determine fractions of tagged photons 155that are modulated by maternal blood, by fitting the parameters ofmodels A and B as described above. Once the parameters are determined,fractions of tagged photons 155 that are modulated by maternal blood andfetal blood can be determined using known methods, for example such asMonte Carlo simulations. Using the results of the simulations, taggedsignal A is calibrated to correspond primarily to fetal contributions.The calibrated signal is then used to extract fetal oxygen saturationlevels as described above.

Turning back to FIG. 3A, it should be noted that the acoustic transducerarrangement may be accommodated such that acoustic waves propagatetowards the fetus along an axis passing between the illuminationassembly and the detection assembly. For example, the transducerarrangement or its associated ultrasound port is located on the samesupport structure 103. The optical unit is preferably operated to startillumination/detection a certain predetermined time after the generationof the acoustic radiation, which is the time needed for the acousticradiation of a given frequency to arrive at the region of interest(fetus). This ensures that light detected by the detection unit 101C isnot affected (tagged) by the acoustic radiation.

Alternatively or additionally, the apparatus of the present invention,for example configured as the above-described apparatus 300, can be usedto monitor the optical properties of the amniotic fluid surrounding thefetus. In this case, a region within the amniotic fluid presents aregion of interest, and as indicated above the term “maternal tissues”refers to regions outside the region of interest. Optical properties ofthe amniotic fluid may include, for example, the absorption coefficient,the scattering coefficient, the reduced scattering coefficient and therefractive index of the fluid. Such optical properties are used tocalculate the concentration of lamellar bodies, blood or meconiumdispersed within the amniotic fluid. The calculated concentration isoptionally compared to a threshold level as described below.

As illustrated schematically in FIG. 3D, to monitor amniotic fluid,apparatus 300A is configured and positioned similar to theabove-described apparatus 300, whereas the region of interest 2A isdefined by a substantial volume of amniotic fluid, being at the shortestoptical path to light output and/or input ports of illumination anddetections assemblies. The substantial volume is that which allows foran overlap of illuminating light and an ultrasound beam within thatvolume. For example, in the case the illumination assembly 101A anddetection unit 101B are appropriately placed to illuminate and collectlight scattered by the amniotic fluid 2A, a transducer arrangement 110is placed such that acoustic waves 150 propagate through the same regionof the amniotic fluid 2A from which scattered photons 155 are detectedby a detection unit 101B. Preferably, the detection assembly isconfigured such that a detection unit 101C collects untagged photonspropagating through maternal tissues 11A (a region outside the region ofinterest), and the detection unit 101B collects tagged and untaggedphotons propagating through a substantial volume of the amniotic fluid(region of interest).

The apparatus 300A may be used for determining the optimal positioningof illumination/detection and ultrasound assemblies, having a pluralityof input and output ports, such that the ultrasound beam is scanned overdifferent locations inside the body and the autocorrelation or powerspectrum of signals generated by each detection unit are determined by acontroller 120 in response to photons scattered from different volumeswithin the body overlapping with the ultrasound beam. As the line-widthof the autocorrelation or power spectrum of the tagged signals, aroundthe frequency of the ultrasound radiation, is different when tagging isperformed inside a fluid volume than when performed in a tissue or bonevolume, the controller 120 can determine, by monitoring the line width,when the ultrasound beam is used to optimally tag a volume of theamniotic fluid.

For monitoring amniotic fluid, the illumination assembly 101A includesone or more light sources generating a plurality of wavelengths (eithersimultaneously or sequentially) from 300 nm to 12 μm. For example, aplurality of wavelengths that are absorbed and/or scattered by lamellarbodies contained in amniotic fluid is chosen for determining theconcentration of lamellar bodies. Preferably, the plurality ofwavelengths is less absorbed by water. Such wavelengths may be chosen inthe range of near infrared, i.e., 600 nm-1300 nm.

At each wavelength, the control unit 120 optionally determines models Aand B (as described above) for the overlaying maternal tissues 11A(region outside the region of interest) and the amniotic fluid (regionof interest), and determines tagged and untagged signal A and untaggedsignal B as described above. Processed tagged signal A and calibratedtagged signal A are used to determine the reduced scattering coefficientand the absorption coefficient of the tagged volume of amniotic fluid asexplained below.

The control unit 120 then determines the concentration of lamellarbodies, blood or meconium in the amniotic fluid. The output of thecontrol unit 120 is displayed on the integrated display or communicatedvia wireless means or cables to another display or electronic processor.Possible outputs include but are not limited to a light signalindicating higher or lower concentration of lamellar bodies relative toa predetermined threshold, a number shown on the display correspondingto the concentration of lamellar bodies in addition to a display of thethreshold number for that value, a sound indicating high or lowconcentration of lamellar bodies relative to a threshold. The controlunit 120 optionally displays a “mature” or “premature” signal, withoutquantitative information about the concentration of lamellar bodies, ordisplays “stained” or “clear” signal for the case of meconium staining.

Lamellar bodies are produced by type II alveolar cells in increasingquantities as fetal lungs mature. They are composed almost entirely ofphospholipid and represent the storage form of the surfactant. Theirdiameter is about 0.5-2 μm, and their index of refraction is about1.475. Consequently, when using the above wavelengths range, it is clearthat Mie scattering dominates the scattering process of light fromlamellar bodies. Choice of specific wavelengths depends on the optimalsignal to noise ratio (SNR) of the apparatus used. The difference inwavelengths used for illumination has to provide a sufficient change inthe scattering coefficient that can be detected by the system. Therelationship between the wavelength and the reduced scatteringcoefficient μ_(s′) of monodisperse scattering dielectric spheres isknown in the literature to be:

$\begin{matrix}{\mu_{s} = {3.28\mspace{11mu}\pi\; a^{2}{\rho\left( \frac{2\;\pi\; a}{\lambda} \right)}^{0.37}\left( {m - 1} \right)^{2.09}}} & \lbrack 5\rbrack\end{matrix}$wherein α is the radius of the dielectric spheres, ρ is their volumedensity, λ is the wavelengths in vacuum, m=n_(s)/n_(o) where n_(s) andn₀ are the refractive indices of the spheres and the surroundingmaterial respectively.

The reduced scattering coefficient μ_(s′) is related to the scatteringcoefficient μ_(s) using the following equation:μ_(s′)=(1−g)μ_(s)   [6]wherein g is the anisotropy factor related to the size and geometry ofthe scattering centers.

Both the reduced scattering coefficient and the scattering coefficientcan be determined according to an embodiment of the present invention.

As an example, light at a plurality of wavelengths is generated by theilluminating assembly 101A. Wavelength selection is based on theabsorption and scattering coefficients of the amniotic fluid. Forexample, amniotic fluid with no blood or meconium absorbs almost equallylight at around 735 nm and 780 nm. Therefore, light distributions insideamniotic fluid at these two wavelengths will differ due to wavelengthdependant changes of the reduced scattering coefficient of the fluid.This reduced scattering coefficient depends on the size, volumeconcentration and relative index of refraction of the lamellar bodies(as evident from equation 5 above). Therefore, by determining thereduced scattering coefficients at different wavelengths, the controlunit 120 determines the concentration of lamellar bodies in the fluidusing equation 5 (or a modified equation 5 which includes physiologicalparameters of lamellar bodies instead of monodisperse spheres).

In order to determine the presence of meconium in the fluid, a differentselection of wavelengths is used. It is known that meconium primarilycontains blood and billirubin, therefore at least two wavelengths areused: one that is absorbed by blood or billirubin (for example 660 nm)and the other that is weakly absorbed by either one of them (for example1064 nm). These wavelengths may for example be used in addition to theabove mentioned wavelengths 735 and 780 nm. Irradiating the amnioticfluid with these two wavelengths (e.g., 660 nm and 1064 nm) will resultin a different light distribution at the shorter wavelengths whenmeconium is present than in the case of no meconium. The absorptioncoefficient of the fluid at these wavelengths is also used to determinethe concentration of meconium in the fluid.

The control unit 120 determines the processed tagged signal A at theplurality of wavelengths used to illuminate the tissues, and stores themin memory. Since the time dependant variations in the optical propertiesof the amniotic fluid are very slow, tagged signal A at each wavelengthcan be integrated over long periods (much longer than the fetal ormaternal heart beats). At those wavelengths, which are absorbed almostequally in the fluid, the variations between the signals obtained atdifferent wavelengths are proportional to the reduced scatteringcoefficient. From these variations of the measured parameters (listedbelow), the control unit 120 determines the reduced scatteringcoefficient.

The control unit 120 determines the reduced scattering coefficient ofthe amniotic fluid by determining, for each illuminating wavelength, atleast one of the following parameters:

(a) The amplitude of the power spectra or autocorrelation of processedtagged signal A corresponding to the frequency of the ultrasound waves;

(b) The line width of the power spectra or autocorrelation of processedtagged signal A (for example, the full width at half max around thefrequency of the ultrasound waves);

(c) The spatial attenuation of the amplitude of the power spectrum oftagged signal A corresponding to the ultrasound frequency.

In the latter case, the ultrasound beam scans the illuminated regionsuch that the overlapping volume, within the amniotic fluid, is variedalong the optical path between the illumination assembly 101A and thedetection unit 101B. For each location, tagged signal A or processedtagged signal A, is stored in memory, and the attenuation of theamplitude of the power spectrum of tagged signal A corresponding to theultrasound frequency is determined.

In order to determine the absorption coefficient, following thedetermination of the reduced scattering coefficient at the abovewavelengths, different wavelengths which are differently absorbed in thefluid (such as 1064 nm or 660 nm) are used and the above parameters aredetermined according to a specific method from those listed above. Theabsorption coefficient depends on the product of the concentration ofthe chromophores or structures within the fluid and the molar absorptioncoefficients (which are known in the literature). In order to determinethe absorption coefficient, following the determination of the reducedscattering coefficient at the above wavelengths (735 nm and 780 nm),different wavelengths which are differently absorbed in the fluid (suchas 1064 nm or 660 nm) are used to illuminate the body region. From thedetermined parameters of the signals at each wavelengths, the opticalattenuation is obtained. The optical attenuation μ_(eff) is known todepend on both the reduced scattering (μ_(s′)) and (μ_(a)) absorptioncoefficients where μ_(eff)=√{square root over (3 μ_(a)(μ_(a)+μ_(s′)))},since the reduced scattering coefficients were determined before, theabsorption coefficients can be extracted.

Therefore, the concentration of absorbing centers (like meconium) isdetermined similar to the concentration of hemoglobin, as describedabove.

In some embodiments of the present invention, a threshold value formature lungs is an input parameter to the control unit 120 prior to itsoperation. In some embodiments of the present invention, severalparameters are being input into the control unit 120 prior to operation.Some parameters are measured by an ultrasound imager, such as, thicknessof uterine wall or thickness of abdominal wall. Additional parametersmay include weight of gravida and duration of gestation (relative tolast menstrual period or based on other indicators). Some of theseparameters are used to calculate the threshold value to which theoptical properties of the amniotic fluid, or the concentration oflamellar bodies, are compared. These parameters can optionally be usedto calculate the concentration of the lamellar bodies from the opticalsignals according to an algorithm that uses the optical properties ofmaternal tissues 11A to extract the optical attenuation in amnioticfluid 2A as explained above.

It should be noted that similar to the configuration of FIG. 2,illumination assembly 101A can be inserted transvaginally to illuminatea volume of amniotic fluid through the cervix. Choice of wavelengths fortranscervical illumination may be different than choice of wavelengthsfor abdominal illumination, since the composition of the differenttissue layers in between the illumination assembly 101A and the amnioticfluid 2A is different for the two configurations. For example, skin(epidermis) contains melanin that highly absorbs in the ultravioletregion, whereas the cervix has little or no melanin.

While it is preferred that the control unit 120 determines theconcentration of lamellar bodies or meconium, it is not always necessaryto determine these concentrations. A database of signals can be definedby recording signals collected by the controller's memory or features ofthese signals (e.g. amplitude, phase, frequency, time dependence,wavelets or principal components). The database may contain data frommeasurement obtained for premature fetal lungs and mature fetal lungs.For lung maturity classification by the database, a similarity metric isdefined. The obtained signals are classified according to the best fitto mature or immature lungs using clustering, neural networks and/orother classification algorithms. For meconium stained analyses, thedatabase can contain signals from stained and clear amniotic fluid.Features from the ultrasound image taken prior or during the assay areused to categorize the measured signals in the database.

Whereas the above examples relate to measuring the optical properties ofamniotic fluid, similar apparatus can be designed for noninvasivemeasuring the optical properties of other extravascular fluids such aspleural (around the lungs), pericardial (around the heart), peritoneal(around the abdominal and pelvis cavities) and synovial (around thejoints) fluids.

Reference is made to FIG. 4 exemplifying a monitoring apparatus 400according to yet another embodiment of the invention. The apparatus isconstructed and operable to enable determining properties of bothmaternal and fetal regions, for example detecting maternal and fetaloxygen saturation levels along with other tissue components. Theapparatus 400 includes a measurement unit (optical and acoustic units)carried by a flexible probe 403; and is connectable to a control unit120. The control unit 120 is similar to the above described controlunit, namely is a computer system including inter alia a power supply, acontrol panel with input/output functions, a display unit, a functiongenerator, electronic circuits, filters and processors, etc.Additionally, the control unit 120 may contain light sources, lightdetectors and acoustic sources. Electric wires, optical fibers and/orwireless means connect the control unit 120 to the elements of themeasurement unit carried by the flexible probe 403. The flexible probe403 includes light output ports 121A and 121B associated with anillumination assembly 101A, and light input ports 122A and 122Bassociated with a detection assembly 101B. It should be understood thatthe elements 121A and 121B carried by the probe 403 may be light sources(such as lasers, laser diodes or LEDs) or the output faces of opticalfibers (or fiber bundles) whose input faces are coupled to light sourcescontained outside the probe, e.g., in the control unit 120. Similarly,elements 122A and 122B may be light detectors (such as for examplediodes or CCD cameras) or the input faces of optical fibers or fiberbundles whose exit faces are coupled to light detectors located outsidethe probe, e.g., contained in the control unit 120. In the case actualdetectors are placed on the flexible probe 403, the detectors arepreferably mechanically and electronically isolated such that acousticwaves propagating from an acoustic output port 245 minimally affect thecollection of photons by the detectors and the transduction of lightsignals into electronic signals. If the ultrasound transducerarrangement 110 is also placed on the probe 403, then the configurationis such as to prevent RF and other electronic signals generated by thetransducer arrangement from interfering with the collection of photonsby the detectors and with the transduction of light signals intoelectronic signals. Such a shielding of the detectors may for exampleinclude electrical isolation by appropriate materials that are poorconductors or create a Faraday cage around a detector, mechanicalisolation by using appropriate material that attenuates the propagationof sheer acoustic waves through the probe itself or through maternaltissues. Detectors may be connected to the probe 403 using connectingparts (possibly detachable) that isolate mechanical and electricalsignals at the frequencies generated by the ultrasound transducerarrangement and at other frequencies.

The detection assembly generates electronic signals in response to theamplitude and phase of photons reaching the input ports 122A and 122B.These electronic signals may be filtered by analog or digital filters,for example bandpass filters, that are appropriately provided beingconnected to the data processing utility of the control unit 120 orbeing a part of this processing utility. The bandwidth of these filterscan be fixed or changed by the control unit 120. Tuning of the bandwidthcan be performed optically by heterodyne detection or by a plurality offilters having different bandwidths, or by tunable filters which arecoupled to each detector. Alternatively, filters can be electronic.

It should be noted that more than two input and output light ports maybe provided in the monitoring apparatus 400, only two pairs of suchports being shown in the present example for the purposes of simplifyingthe illustration. In addition, each port may serve as a dual input andoutput light port by using a fiber combiner/splitter that couples lightinto and out of one optical fiber. The ports may be arranged in aone-dimensional array or a two-dimensional array to improve flexibilityof use.

Preferably, the input and output ports are arranged such that an equaloptical path through body tissues exists between pairs of output andinput ports. For example, light input and output ports are arranged suchthat they are not. coplanar, but rather form sets of isosceles trianglesbetween output and input ports, having equal light paths between oneoutput port and two input ports (or vice versa).

The flexible probe 403 also contains the ultrasound output port 245 fromwhich acoustic waves 255 (shown as semicircles 255) are directed towardsthe region of interest. Acoustic waves 255 are generated by theultrasound transducer arrangement 110 that may be located on theflexible probe 403 and connected to a function generator in the controlunit 120 using electric wires 236 or using wireless means.Alternatively, the ultrasound transducer 110 may be located outside theprobe 403, e.g., in the control unit 120, and acoustic waves betransmitted to the output port 245 using suitable acoustic waveguides236. In the example of FIG. 4, the output port 245 is located betweenthe light input and output ports. The output port 245 may be placed atany location of the flexible probe 403 (i.e. to the right of output port121A or the left of input port 122A). Several ultrasound output ports,at different locations along the flexible probe 403, may be used beingcoupled to the same ultrasound transducer arrangement or to differentultrasound transducer arrangements.

When different ultrasound transducer arrangements are used, thetransducer arrangements may generate acoustic waves of the samefrequency modulation, or each may generate a different frequencymodulation. When different frequencies are being generated, the controlunit 120 controls the modulation at each transducer arrangementaccording to the spatial locations of each output port associated witheach transducer arrangement, such that light propagating through thesame volume as the acoustic waves and collected through one or severallight input ports is analyzed based on the correct frequency modulationof the corresponding transducer arrangement (as will be described belowfor one such transducer arrangement). Different transducer arrangementscan generate acoustic waves at the same time intervals, or duringdifferent time intervals.

The flexible probe 403 is placed in contact with a maternal skin 10 in aregion overlaying a fetal tissue 2 contained in maternal tissues. Thepositioning of the flexible probe 403 may be performed with the aid ofan ultrasound imaging system that is used to determine the optimallocation of light ports and acoustic output port relative to the fetus(as described above). Different fetal organs or tissues can be used tomonitor fetal oxygen saturation including the placenta.

The flexible probe 403 is placed in contact with the maternal skin 10using adhesive pads or by applying pressure to maternal abdomen using abelt. The acoustic output port 245 is coupled to the skin 10 using anacoustic coupling material such as gel or a hyrdrogel adhesive.

Upon attachment of the probe 403, the control unit 120 is turned on in acalibration mode. During the calibration mode, the control unit 120sends an electronic signal to the function generator connected to theultrasound transducer arrangement causing it to generate a series ofacoustic pulses. The acoustic pulses are transmitted through theultrasound output port 245 and propagate through maternal tissues 11 andfetal tissues 2. A portion of the acoustic pulses is reflected from eachsurface or impedance mismatched layer that the pulses encounter duringtheir propagation. The reflected portion is collected through theacoustic output port 245 and transmitted to an ultrasound transducer ofthe imaging system (which may be the same transducer arrangement 110used for measurements). The transducer arrangement used for imaging maybe a single acoustic transmitter, a single acoustic transceiver, anarray of transmitters and/or receivers, an ultrasound Doppler imager, aphased array, or a complete imaging system capable of transmitting andreceiving acoustic signals. The control unit 120 analyzes the signalsgenerated by the transducer in response to the portion of reflectedpulses and determines a distance between the ultrasound output port 245and the fetal tissues 2 (by multiplying the speed of sound in the tissueby half the time difference Δτ between the emission of the acousticpulses from the output port 245 and the collection of the reflectedpulses in the said port 245).

The control unit 120 then determines an appropriate distance to beprovided between the light output port 121A or 121B and the light inputport 122A or 122B, such that photons 250 emitted from the output port121A will propagate through fetal tissues 2 before reaching the inputport 122A or 122B. The control unit 120 can select which output andinput ports are used from a plurality of light ports arranged atdifferent spatial locations, such that at least one input port collectsphotons, emitted from at least one output port, that propagate throughthe same fetal tissue 2 through which acoustic waves 255 propagate. Thecontrol unit 120 also determines which of the other light input portscollect photons that propagate through maternal tissues 11 and notthrough fetal tissues 2. Additionally, during the calibration mode, thecontrol unit 120 determines a desired frequency bandwidth Δf₁ that is tobe used during the monitoring. For example, the control unit 120 selectsthe frequency bandwidth Δf₁ corresponding to that optimally filtered byanalog or digital electronic filters connected to the light detectors.

Following the calibration mode, the control unit 120 operates an arrayof fixed output and input light ports by modulating (including timegating) the light sources connected only to the chosen output ports, ormodulating the output ports themselves, and analyzing the signalsgenerated by the detectors coupled to the chosen input ports.

As indicated above, the control unit 120 determines the desiredfrequency bandwidth Δf₁ to be used during the monitoring as thatcorresponding to a frequency bandwidth optimally filtered by analog ordigital electronic filters connected to the light detectors. Thebandwidth that these filters optimally transmit is fixed or varied bythe control unit 120 during the operation of the apparatus 400. Thecontrol unit 120 controls a portion of the frequency bandwidth generatedby the function generator to correspond to the frequency bandwidth thatis optimally transmittable by the electronic filters connected to thelight detectors. Alternatively, the bandwidth of the filters is variedby the control unit 120 to correspond to a portion of the frequencybandwidth generated by the function generator. The control unit 120 alsocontrols the frequency modulation of acoustic waves 255 such that waveshaving a frequency outside the frequency bandwidth Δf₁ are for examplegenerated during different portions of the acoustic pulse.

The control unit 120 controls the time dependent generation of thefrequency modulated acoustic waves. The control unit 120 determines atime period Δt₁ needed for signal acquisition such that optimalsignal-to-noise ratio (SNR) for determining fetal oxygen saturation isobtained during the measurements. The time period Δt₁ is shorter than atime difference between the fetal heart beats, when pulse oximetry isused for data analysis. The control unit 120 also determines thefrequency modulation parameters such that the desired frequencybandwidth Δf₁, (or phase) propagates through the fetal tissue 2 duringthe time period Δt₁. The onset of time period is at time t₁ equal toabout Δτ/2 where the acoustic pulse reaches the fetal tissues 2 and timet₂ is determined by t₂=t₁+Δt₁.

In the present example of FIG. 4, the operation of apparatus 400 in a“monitor mode” or actual measurement mode is shown. During the monitormode, the control unit 120 activates the light source(s) associated withthe output port 121A to emit photons 250 and 251, and actuates the lightsource(s) associated with the output port 121B to emit photons 252. Thelight ports may be associated with different light sources or with oneor more common light sources. A single light source and preferably twolight sources, emitting light of at least two different wavelengthssimultaneously, are connected to the output ports, whereas one lightsource may be connected to more than one output port. Light sourcesconnected to different output ports, or output ports themselves, may beactivated during different time periods or with differentcharacteristics (such as different modulation frequency or phase), suchthat the control unit 120 can distinguish between photons 251 and 252reaching input port 122B of the detection unit.

The control unit 120 also activates a function generator that, in turn,activates the ultrasound transducer arrangement 110 to generate acousticwaves 255 transmitted through the output port 245. The acoustic wavefrequency (or phase) generated by the function generator is modulated bythe control unit 120 such that the acoustic waves reaching a region ofthe fetal tissue 2 illuminated by photons 250 will have a predeterminedfrequency bandwidth Δf₁. If the bandwidth Δf₁ is fixed, then the controlunit 120 determines the frequency modulation of the function generatorcontrolling the generation of ultrasound waves 255, such that acousticwaves 255 modulated at a frequency within Δf₁ reach the fetal tissues 2at time t₁. In addition, acoustic waves with a frequency within Δf₁substantially do not propagate through other tissues during the timeperiod Δt₁ following time t₁. Accordingly, the control unit operates thedetection assembly such that the light detectors associated with theinput ports 122A and 122B start collection of photons at time t₁ and endthe collection process during t₂. Alternatively or additionally, thecontrol unit 120 controls the activation of light sources associatedwith the output ports 121A and/or 121B at time t₁ and ends theactivation at time t₂. During the time period Δt₁, the input port 122Aand/or input port 122B collect photons propagating through the samefetal tissues through which acoustic waves 255 propagate (a time delayin photon propagation through the tissue is neglected).

FIG. 5 exemplifies a monitoring apparatus 500 of a somewhat differentconfiguration. Apparatus 500 differs from the above-described apparatus400 in the arrangement of input and output ports (or light sources anddetectors) within a flexible probe 403. Here, light port 121A′ functionsas an output port (associated with the illumination assembly), lightports 121B′ and 122A′ function as both output and input ports(associated with the illumination assembly and detection unit), andlight port 122B′ functions as an input port (associated with thedetection unit).

In addition, all input ports may be time gated to collect lightpropagating through specific tissues during a certain time period.Additionally or alternatively, the output ports may be activated duringdifferent time intervals. For example, the input ports 121B′ or 122B′are activated during a time interval Δt_(g), following the introductionof light from the output ports 121A′ or 122A′, respectively, such thatonly photons 256 propagating from the output port 121A′ to the inputport 121B′ or photons 257 propagating from the output port 122A′ to theinput port 122B′ are collected during that time interval. The outputports 121A′ and 122A′ are therefore activated at different timeintervals, such that the input port 122B′ does not collect photons 251and 257 simultaneously. During a time interval Δt_(k), different fromΔt_(g), the input port 122A′ is activated, following the introduction oflight from the output ports 121A′, such that only photons 250propagating through fetal tissues 2, are detected. As will be explainedbelow, during the time interval Δt_(g) the light input ports collectlight propagating primarily through maternal tissues, being untagged.During time interval Δt_(g) acoustic waves 255 do not propagate throughthe same volume from which light is collected by the input ports 121B′and 122B′. During time interval Δt_(k) the light input ports collectlight propagating primarily through maternal and fetal tissues, beingtagged or untagged.

It is preferred that the time interval Δt_(k) corresponds to the timeinterval Δt₁ defined above, where both intervals start at t₁. It ispreferred that the intervals Δt_(k) and Δt_(g) are closely spaced intime such that no substantial modulation in blood or tissuecharacteristics occurs in between these time intervals.

Alternatively, several light input ports may be activated duringdifferent time intervals corresponding to light propagation througheither maternal tissues alone or maternal and fetal tissues, anddifferent acoustic waves can optionally propagate through all volumesfrom which light is collected allowing both tagged and untagged light tobe analyzed through every input port.

Tagged and untagged signals collected by all the input ports are used todetermine the fetal oxygen saturation level based on the tissue models Aand B, described above. The amplitudes of the tagged and untaggedsignals are, determined during the time intervals Δt_(k) and Δt_(g)respectively.

The filtered electronic signal at a selected bandwidth Δf₁, during thetime period Δt₁, starting at t₁, corresponds to the amplitude of thetagged signal propagating through the fetal tissue 2. Photons 250propagating through other tissue regions, during the time period Δt₁,where the frequency of the ultrasound waves 255 is outside the frequencybandwidth Δf₁, will have a different modulation frequency and will beattenuated by the filters having the bandwidth of Δf₁. The electronicfilters connected to the light detectors can have several bandwidths ofoptimal transmission (Δf₂ . . . . Δf_(n)) different from Δf₁. Detectorsare configured such that during each time period Δt_(i) (i=1 . . . n)starting at time t_(i), where t_(i) is the time where portion ofacoustic pulse having a frequency modulation with a bandwidth Δf_(i)reaches the fetal tissue 2, the detectors are tuned to optimally convertphotons, modulated by frequency Δf_(i), to electrical signals.

For example, as the modulated ultrasound waves propagate throughmaternal and fetal tissues, at different time periods (Δt₂ . . . Δt_(n))different from Δt₁, acoustic waves at different frequency modulationspropagate through the fetal tissues. The control unit 120 then operateseach filter according to the order and duration of the differentfrequency modulations within the ultrasound pulse, such that eachelectronic filter having a frequency bandwidth Δf_(i) is activated attime periods Δt_(i) starting at t_(i) in accordance with thecorresponding frequency bandwidth of the ultrasound wave. Additionally,the electronic filter can have a variable bandwidth that is controlledby the control unit 120 in accordance with the generation of thefrequency modulation of the ultrasound wave. The control unit 120 thenintegrates the electronic signals generated by the light detectors andfiltered by the electronic filters at all frequency bandwidths duringthe corresponding time periods. The control unit 120 then analyzessignals received from the electronic filters to determine the fetaland/or maternal oxygen saturation levels.

Referring to either one to FIGS. 4 and 5, the control unit 120 analyzestagged signals, reaching at least one of the input ports of thedetection units and being modulated at frequency bandwidth Δf_(m)different from Δf_(i) (i=1 . . . n), during a time period Δt_(i)starting at t_(i), to determine the properties of maternal tissuesthrough which photons 251 and/or 252 (in FIG. 4) propagate. Thesesignals may optionally be used to determine maternal oxygen saturationlevels. The control unit 120 then uses the tagged signals having amodulation corresponding to frequency bandwidth Δf_(m) in model Bdescribed above to determine characteristics of maternal tissues. Thecontrol unit 120 then calibrates model A as described above. The controlunit 120 then uses tagged signals, reaching the input ports of thedetection units and being modulated at the frequency bandwidthcorresponding to Δf_(i) during the same time period Δt_(i) starting att_(i) in accordance with model A to determine fetal oxygen saturationlevels.

It should be noted with respect to the above-described examples, thatthe transducer arrangement 110 may include an ultrasound imaging systemand/or and ultrasound Doppler imager, such that ultrasound images orDoppler signals are acquired during operation of the monitoringapparatus. Prior to and during the operation, an ultrasound image oftissues including the region of interest is first acquired. The controlunit 120 (or the operator) identifies the region of interest by markingthis region on the first acquired ultrasound image. Transducerarrangement 110 is then fixed at the same location (by the operator orby using an adhesive), for duration necessary to obtain efficient taggedsignals from the region of interest. The control unit 120 determines thecorresponding distance, angle and size of the region of interestrelative to the transducer arrangement 110. Then, the control unit 120operates to select input and output light ports to emit light andcollect light propagating through the region of interest and the outsideregion, as described above (i.e., to ensure optimal positioning duringthe measurements). The control unit 120 synchronizes the activation ofthe light output ports and/or light input ports such that emission ofultrasound pulses to the region of interest corresponds to thepropagation of light pulses through the region of interest.Alternatively, the control unit 120 synchronizes the emission ofacoustic pulses by the transducer arrangement 110 such that the onset,duration and direction of these pulses correspond to the onset andduration of the activation of light input and/or output ports. Thecontrol unit 120 analyzes tagged and untagged signals generated by thedetection assembly and determines the concentration of an analyte (forexample, oxygenated hemoglobin) in the region of interest, as describedabove. More -than one analyte can be monitored simultaneously by usingdifferent wavelengths of light, each having a characteristic absorptionor scattering by the selected analytes. The control unit 120 thendisplays simultaneously (using, for example, color coded images) thelocal concentration of the analyte on the region of interest of theultrasound image, in addition to any other form of display (e.g.numerical) that is understood by the operator and/or by a machineconnected to the control unit 120. In cases where more than oneultrasound pulse is needed for obtaining efficient tagged light signals,the transducer arrangement is operated without scanning the ultrasoundbeam, and a single beam is emitted in the direction of the region ofinterest for the duration needed for an efficient tagged signalacquisition. Yet another option suitable for cases when the transducerarrangement is moved during operation, such that distances and anglesbetween the transducer arrangement 110 and the region of interest arechanged, the control unit 120 tracks the position of the region ofinterest using techniques and algorithms such as of three-dimensionalultrasound imaging (F. Rousseau, P. Hellier, C. Barillot, “CalibrationMethod for 3D Freehand Ultrasound”, In Medical Image Computing andComputer Assisted Intervention, MICCAI'03, Montreal, Canada, November2003). The control unit 120 then determines the changed distance andangle to the region of interest, and dynamically selects and activatescorresponding input and output light ports accordingly during themovement of the transducer arrangement 110.

In another embodiment of the invention, an imaging apparatus may be usedto monitor changes in the concentration of analyte(s) in a region ofinterest during therapeutic or surgical procedures (such as during theapplication of high power ultrasound pulses or wave, laser ablation, orchemical procedures). For example, the transducer arrangement 110 may beused for ablation of tumors or malformations in a tissue. During theapplication of high power ultrasound pulses, light is emitted andcollected by illumination and detection assemblies, respectively, todetermine the concentration of an analyte indicative of the treatment inthe region being ablated. Alternatively, low power ultrasound pulses(that do not cause ablation) intermittently irradiate the region ofinterest, while low-power light pulses are emitted and collected byillumination and detection assemblies to determine the concentration ofan analyte indicative of the treatment. For example, oxygenation of theregion of interest is monitored. Such information is used forcontrolling and monitoring the treatment during application ofultrasound radiation.

Reference is now made to FIGS. 6A and 6B exemplify yet anotherconfiguration of a flexible probe, generally designated 603, suitable tobe used in either one of the above described monitoring apparatuses. Theflexible probe 603 includes a flexible support 301, for example made ofelectrically isolating material(s), carrying light ports 303-316(fiber-ends in appropriate housing, or light sources and/or lightdetectors as described above) and an acoustic output port 302 (oracoustic transducer arrangement). FIG. 6A presents a bottom view of theflexible probe 603 viewed from the side by which it is attachable to askin, and FIG. 6B shows a side view diagram of the flexible probe 603.Optical fibers or electric wires 330-336 and 340-346 connect the lightports 310-316 and 303-309, respectively, to a common connector 320. Anisolated electric cable (or acoustic waveguides) connects the acousticoutput port 302 to the same connector 320 associated with a controlunit. The acoustic port 302 is preferably coupled to an ultrasoundtransducer arrangement 327 connected to the flexible support 301 usingvibration controlling elements. The connector 320 couples the opticalfibers and cables attached to the flexible support 301 with opticalfibers and electric cables coupled to the control unit (not shown here).The connector 320 may be composed of several connector elements. Anadhesive 325 is attached to the bottom side of the support 301, suchthat the probe 603 can be fixed to the skin using this adhesive 325.Adhesive 325 is preferably transparent and produces minimal scatteringin a wavelength range used for measurements (i.e., emitted by lightsources). Alternatively or additionally, the adhesive 325 may form anoptical index matching layer between the light ports and the skin.Alternatively, the adhesive 325 may not cover the light ports at all, ormay partially cover them. The adhesive 325 may contain pigments,chromophores or other materials for controlling the transmission ofdifferent wavelengths of light. An adhesive gel 326 is located below theacoustic port 302. The adhesive gel 326 is made from the same ordifferent material as the adhesive 325 and is designed for optimalacoustic coupling between the acoustic port 302 and the skin. Possiblematerials for adhesives 325 and 326 include hydrogel based adhesives.

The different elements of the flexible probe 603 may be assembled indifferent ways. For example, the complete probe 603 is assembled priorto operation, and a user only needs to remove a thin layer covering thebottom side of adhesives 325 and 326. In yet another example, theadhesive 326 is attached to the acoustic output port 302 (preferablyincluding the acoustic transducer arrangement itself) which is notattached to the probe 603 prior to the device operation. The user firstattaches the flexible support 301 to the skin using the adhesive 325,and then inserts the acoustic port 302 through an appropriately providedopening in the support 301, where the transducer 327 is optionallyconnected to the support 301 using conventional means and is attached tothe skin using the adhesive 326. The latter may be part of adhesive 325,and only the acoustic output port 302 is inserted and attached to theupper part of the adhesive 326 (being a double sided adhesive). The userfirst attaches the adhesives 325 and 326 to skin, then attaches theacoustic port 302 to the adhesive 326, and then connects the support 301to the upper side of the adhesive 325 (being a double sided adhesive).Finally, the connector 320 is connected to the cables and fibers fromthe control unit to allow the operation of the probe. Each element ofthe flexible probe 603 and the complete probe 603 as a unit may be usedonly once and then discarded (i.e., is disposable), or used multipletimes.

FIGS. 7A and 7B show yet another example of a flexible probe 703according to the present invention. Here, a support 301 carries lightports (or light sources) and several acoustic ports 302, 319 and 319A(or acoustic transducer arrangements). Each of the acoustic ports 302,319 and 319A is coupled to a connector 320 using cables 338, 339 and339A, respectively. Adhesive gels 326, 329 and 329A are used to couplethe acoustic ports 302, 319 and 319A, respectively, to the skin.Similarly, each of the acoustic ports may be separated from the probe703 when not in use, and inserted by user for as preparation foroperation.

Those skilled in the art will readily appreciate that variousmodifications and changes may be applied to the embodiments of theinvention as hereinbefore described without departing from its scopedefined in and by the appended claims.

The invention claimed is:
 1. A monitoring system for use innon-invasively monitoring at least one parameter of a region of interestin a human body, the system comprising: a measurement unit comprising:an optical unit having an illumination assembly configured to define atleast one output port for illuminating light, and a light detectionassembly configured to define at least one light input port forcollecting light scattered from the illuminated body portion and togenerate measured data indicative of the collected light; and anacoustic unit configured to generate acoustic waves of a predeterminedultrasound frequency range; the measurement unit being configured andoperable to provide an operating condition such that the acoustic wavesof the predetermined frequency range overlap with an illuminating regionwithin the region of interest and substantially do not overlap with aregion outside the region of interest, and that the detection assemblycollects light scattered from the region of interest and light scatteredfrom the region outside the region of interest, the measured data beingthereby indicative of scattered light having both ultrasound tagged anduntagged light portions; and a control unit, which is connectable to theoptical unit and to the acoustic unit to operate these units, thecontrol unit being responsive to the measured data and preprogrammed to:process and analyze the measured data to extract therefrom a dataportion associated with the light response of the region of interest anddetermine said at least one parameter of the region of interest, by:interpreting the tagged light portions as having been at least partiallyscattered by the region of interest, interpreting the untagged lightportions as having been scattered by the region outside of the region ofinterest, and extracting, from the tagged light portion of the measureddata, the data portion associated with the light response of the regionof interest, based on the untagged light portions of the measured data.2. The system of claim 1, wherein the acoustic unit is configured forgenerating ultrasound radiation selected from the group consisting of:unfocused radiation, and focused radiation with a focal lengthcorresponding to a distance from the acoustic unit to the region ofinterest.
 3. The system of claim 1, wherein the control unit isconfigured to determine oxygen saturation of the region of interest. 4.The system of claim 1, wherein the control unit is configured to utilizeprinciples of oximetry or pulse oximetry to determine the desiredparameter of the region of interest.
 5. The system of claim 1, whereinthe measurement unit is configured and operable to generate the measureddata indicative of variations of the ultrasound tagged light portion asa function of at least one of time and wavelength of the illuminatinglight, the control unit being configured to analyze the variations ofthe ultrasound tagged light portion to determine at least onepredetermined characteristic of the portion and calculate oxygensaturation, said at least one predetermined characteristic of theportion including maxima, minima and average of the portion.
 6. Thesystem of claim 1, wherein the control unit is preprogrammed andoperable to provide optimal positioning of the optical unit and theacoustic unit, said optimal positioning satisfying said operatingcondition.
 7. The system of claim 6, wherein the control unit isoperable to provide a relative displacement between a direction ofpropagation of the acoustic radiation and at least one of theillumination and detection assemblies so as to provide said optimalpositioning.
 8. The system of claim 7, wherein the control unit isoperable to displace at least one of the light input or output portswith respect to the direction of the acoustic waves propagation.
 9. Thesystem of claim 1, wherein the illumination assembly is configured todefine at least two spaced-apart light output ports.
 10. The system ofclaim 9, wherein the control unit is operable to select at least one ofthe light output ports for measurements, to provide said operatingcondition.
 11. The system of claim 10, wherein the detection assembly isconfigured to define at least two spaced-apart light input ports. 12.The system of claim 11, wherein the control unit is operable to selectat least one of the light input ports for measurements, to provide saidoperating condition.
 13. The system of claim 1, wherein the detectionassembly has a configurations selected from the group consisting of: (a)a configuration in which the detection assembly is configured to defineat least two spaced-apart light input ports; and (b) a configuration inwhich the detection assembly is configured to define an array of atleast two spaced-apart light input ports, such that when in theoperating condition, at least one of the light input ports collects thetagged light coming from the region of interest, and at least one otherof the light input ports collects the untagged light scattered from theregion outside the region of interest.
 14. The system of claim 13,wherein the control unit is preprogrammed for operating at least one ofthe light input ports a predetermined time after the operation of theacoustic unit, thereby providing said operating condition.
 15. Thesystem of claim 14, wherein said predetermined time corresponds to atime needed for the acoustic waves of the predetermined frequency rangeto reach the region where the overlapping with the illuminating light isto be provided.
 16. The system of claim 15, wherein said at least one ofthe light input ports is located proximate of the light output portthereby collecting untagged light scattered from the region outside ofthe region of interest; and said at least one other light input port islocated at a larger distance from the light output port as compared to alocation of at least one other light input port thereby collectingtagged light coming from the region of interest through the regionoutside of the region of interest.
 17. The system of claim 16, whereinthe control unit is preprogrammed to process and analyze a first set ofmeasured data generated by said at least one light input port todetermine data indicative of a characteristic of a light response of theregion outside of the region of interest to the illuminating light; andto utilize said first set of data indicative of the light responsecharacteristic in the processing and analyzing of a second set ofmeasured data generated by said at least one other input port to therebyextract the light response of the region of interest.
 18. The system ofclaim 13, wherein the control unit is operable to select at least one ofthe light input ports for measurements, to provide said operatingcondition.
 19. The system of claim 13, wherein said at least two lightinput ports are arranged such that at least one of the light input portsis located proximate of the light output port thereby collectinguntagged light scattered from the region outside of the region ofinterest; and the at least one other light input port is located at alarger distance from the light output port thereby collecting ultrasoundtagged light coming from the region of interest through the outsideregion.
 20. The system of claim 19, wherein the control unit ispreprogrammed to process and analyze a first set of measured datagenerated by said at least one light input port to determine dataindicative of a characteristic of a light response of the region outsideof the region of interest to the illuminating light; and to utilize saidfirst set of measured data indicative of the light responsecharacteristic in the processing and analyzing of a second set ofmeasured data generated by said at least one other input port to therebyextract the light response of the region of interest.
 21. The system ofclaim 1, wherein the illumination assembly is configured and operable togenerate the illuminating light of at least two different wavelengths.22. The system of claim 21, wherein the illumination assembly isoperable to generate said at least two different wavelengths atdifferent times.
 23. The system of claim 22, wherein the at illuminationassembly is operable to generate the at least two wavelengths, thewavelengths being differently modulated by at least one characteristicselected from the group consisting of frequency and phasecharacteristics.
 24. The system of claim 21, wherein the illuminationassembly is operable to generate the at least two wavelengths, thewavelengths being differently modulated by at least one characteristicselected from the group consisting of frequency and phasecharacteristics.
 25. The system of claim 21, wherein the illuminationassembly is configured and operable to generate the illuminating lightof at least three different wavelengths, of which two of the wavelengthsare characterized, with respect to one another, by having the sameabsorption by tissue or fluid components in the body and as beingdifferently scattered by the tissue or fluid components in the body, andof which two of the wavelengths are characterized, with respect to oneanother, by having different absorption by the tissue or fluidcomponents in the body.
 26. The system of claim 1, wherein the detectionassembly is configured to define the light input port which, when in theoperating condition, detects both the light scattered from the region ofinterest and the light scattered from the outside of the region ofinterest.
 27. The system of claim 1, wherein the control unit ispreprogrammed for operating the optical unit a predetermined time afterthe operation of the acoustic unit, thereby providing said operatingcondition.
 28. The system of claim 27, wherein said control unit ispreprogrammed such that said predetermined time corresponds to a timeneeded for the acoustic waves of the predetermined frequency to reachthe region where the overlapping with the illuminating light is to beprovided.
 29. The system of claim 1, wherein the control unit isconfigured and operable to actuate the optical and acoustic units toirradiate with the acoustic radiation a plurality of regions in theilluminated part of the body and detect scattered photons; and toanalyze the measured data to identify tagged and untagged light portionsassociated with each of said plurality of regions to determine aparameter indicative of the light response of each of said plurality ofregions, thereby enabling identification of said region of interest. 30.The system of claim 1, comprising a support structure carrying at leastthe light output and light input ports of the illumination and detectionassemblies.
 31. The system of claim 30, wherein said support structurehas at least one configuration selected from the group consisting of:(i) a configuration in which the support structure is configured forcarrying the illumination and detection assemblies; (ii) a configurationin which the support structure is configured for carrying the acousticunit; (iii) a configuration in which the support structure is configuredfor carrying an output port of the acoustic unit; and (iv) aconfiguration in which the support structure is flexible to wrap aroundthe body portion.
 32. The system of claim 1, wherein the acoustic unitis configured for generating ultrasound radiation in a form selectedfrom the group consisting of: continuous wave, pulse, and burst.
 33. Thesystem of claim 1, wherein the control unit is configured and operableto apply a frequency filtering to the output of the detection assemblyto correspond to a frequency bandwidth of the acoustic waves irradiatingthe region of interest.
 34. The system of claim 1, wherein the acousticunit comprises a phased array of ultrasound transducers.
 35. The systemof claim 1, wherein the control unit is configured for carrying out atleast one technique selected from the group consisting of: receivingdata indicative of reflections of the ultrasound waves from anirradiated volume inside of the body for creating data indicative of animage of the irradiated volume, and analyzing said image data to providesaid operating condition for measurements; and receiving data indicativeof reflections of the ultrasound waves from an irradiated volume insidethe body for determining data indicative of a Doppler shift in theultrasound radiation reflections.
 36. The system of claim 1, whereinsaid predetermined frequency range of the ultrasound radiation is from50 kHz to 8 MHz.
 37. The system of claim 1, wherein the ultrasoundradiation is of a frequency lower than 1 MHz.
 38. The system of claim 1,wherein the system is configured for use in monitoring at least oneparameter selected from the group consisting of: oxygen saturation levelof the region of interest, and concentration of a substance or structurein the region of interest.
 39. A method for use in noninvasivemonitoring at least one parameter of a region of interest in a humanbody, the method comprising: operating an optical unit and an acousticunit so as to provide that ultrasound waves of a predetermined frequencyrange and illuminating light overlap within the region of interest andsubstantially do not overlap with a region outside the region ofinterest, thereby producing measured data indicative of collected lightincluding scattered light having ultrasound tagged and untagged lightportions, interpreting the tagged light portions as having been at leastpartially scattered by the region of interest, interpreting the untaggedlight portions as having been scattered by the region outside of theregion of interest, and extracting, from the tagged light portion of themeasured data, the data portion associated with the light response ofthe region of interest, based on the untagged light portions of themeasured data.
 40. The method of claim 39, wherein operating theacoustic unit comprises irradiating the region of interest withunfocused or focused ultrasound radiation.
 41. The method of claim 39,further comprising determining oxygen saturation of the region ofinterest, based upon the extracted data portion.
 42. The method of claim39, further comprising utilizing principles of oximetry or pulseoximetry to determine the parameter of the region of interest, basedupon the extracted data portion.
 43. The method of claim 39, whereinoperating the optical unit comprises applying the illumination of atleast two different wavelengths, and producing measured data indicativeof variations of the ultrasound tagged light portion as a function of atleast one parameter selected from the group consisting of time andwavelength of the illuminating light.
 44. The method of claim 43,further comprising analyzing the time variations to determine at leastone predetermined characteristic of the tagged light portion andcalculate oxygen saturation of the region of interest, said at least onepredetermined characteristic being selected from the group consisting ofmaxima, minima and average of the portion.
 45. The method of claim 39,wherein operating the optical unit and the acoustic unit comprisesproviding a relative displacement between a direction of propagation ofthe acoustic radiation and at least one assembly selected from the groupconsisting of: an illumination assembly and detection assembly of theoptical unit.
 46. The method of claim 45, wherein operating the opticalunit and the acoustic unit comprises displacing at least one of lightinput or light output ports of the optical unit with respect to thedirection of the acoustic waves propagation.
 47. The method of claim 45,wherein operating the optical unit and the acoustic unit comprisescarrying out a technique selected from the group consisting of: (a)inserting the acoustic unit into the body through an opening, andlocating the optical unit outside the body, during a monitoringprocedure; and (b) inserting the optical unit into the body through anopening, and locating the acoustic unit outside the body, during amonitoring procedure.
 48. The method of claim 47, wherein the openingincludes a vaginal tract, the method comprising inserting into thevaginal tract a unit selected from the group consisting of the acousticunit and the optical unit.
 49. The method of claim 39, wherein operatingthe optical unit comprises selecting for measurements at least one lightoutput port, from a plurality of spaced-apart light output ports, of theoptical unit.
 50. The method of claim 49, wherein operating the opticalunit comprises selecting for measurements at least one light input portfrom a plurality of spaced-apart light input ports of the optical unit.51. The method of claim 39, wherein operating the optical unit comprisesselecting for measurements at least one light input port from aplurality of spaced-apart light input ports of the optical unit.
 52. Themethod of claim 39, wherein operating the acoustic unit comprisesapplying ultrasound imaging to the region of interest surrounded by theoutside region.
 53. The method of claim 52, wherein applying theultrasound imaging comprises applying the ultrasound imaging using saidacoustic unit.
 54. The method of claim 39, wherein extracting, from thetagged light portion of the measured data, the data portion associatedwith the light response of the region of interest comprises monitoringat least one parameter of the region of interest during therapeuticapplication of ultrasound radiation or light radiation thereto.
 55. Themethod of claim 54, further comprising applying the therapeuticultrasound radiation using said acoustic unit.
 56. The method of claim39, further comprising detecting reflections of the ultrasound radiationfrom the irradiated body portion and determining a Doppler shift in thedetected reflections.
 57. The method of claim 39, wherein operating theoptical unit comprises operating an illumination assembly of the opticalunit to carry out a technique selected from the group consisting of: (a)generating the illuminating light of at least two different wavelengths;(b) generating the illuminating light of at least two differentwavelengths at different times; and (c) generating the illuminatinglight of at least two different wavelengths differently modulated by atleast one of frequency and phase characteristics.
 58. The methodaccording to claim 57, wherein operating the optical unit comprisesoperating an illumination assembly of the optical unit to generate theilluminating light of at least three different wavelengths, of which twoof the wavelengths are characterized, with respect to one another, byhaving the same absorption by tissue or fluid components in the body andas being differently scattered by the tissue or fluid components in thebody, and of which two of the wavelengths are characterized, withrespect to one another, by having different absorption by the tissue orfluid components in the body.
 59. The method of claim 39, furthercomprising detecting both the light scattered from the region ofinterest and the light scattered from the outside of the region ofinterest.
 60. The method of claim 39, wherein operating the optical unitand the acoustic unit comprises operating at least two spaced-apartlight input ports of the optical unit to provide at least one lightcollection condition selected from the group consisting of: (i) at leastone of the light input ports collects the light scattered from theregion of interest, and at least one other of the light input portscollects the light scattered from the outside region; (ii) at least oneof the light input ports collects the untagged light scattered from theregion outside the region of interest, and at least one other of thelight input ports collects the tagged light coming from the region ofinterest through the region outside the region of interest.
 61. Themethod of claim 60, wherein operating the optical unit and the acousticunit comprises collecting the untagged light scattered from the regionoutside of the region of interest by said at least one light input portlocated proximate of the light output port, and collecting the taggedlight coming from the region of interest through the region outside theregion of interest by said at least one other light input port locatedat a larger distance from the light output port.
 62. The method of claim61, wherein extracting, from the tagged light portion of the measureddata, the data portion associated with the light response of the regionof interest, based on the untagged light portion of the measured datacomprises: processing and analyzing a first set of measured datagenerated by said at least one light input port to determine dataindicative of a characteristic of a light response of the region outsidethe region of interest to the illuminating light; and utilizing saidfirst set of measured data indicative of the light responsecharacteristic in processing and analyzing of a second set of measureddata generated by said at least one other light input port, to therebyextract from the second measured data the data indicative of the lightresponse of the region of interest.
 63. The method of claim 39, whereinoperating the optical unit and the acoustic unit comprises operating theoptical unit a predetermined time after the operation of the acousticunit, said predetermined time corresponding to a time needed for theacoustic waves of the predetermined frequency range to reach the regionof interest where the overlapping with the illumination light is to beprovided.
 64. The method of claim 39, wherein said at least oneparameter includes at least one parameter selected from the groupconsisting of: oxygen saturation level; and concentration of a substrateor structure in the region of interest; and wherein extracting, from thetagged light portion of the measured data, the data portion associatedwith the light response of the region of interest comprises facilitatingmonitoring of the selected parameter.
 65. The method of claim 39,wherein extracting, from the tagged light portion of the measured data,the data portion associated with the light response of the region ofinterest comprises facilitating noninvasive monitoring of a fetuscondition.
 66. The method of claim 65, wherein said at least oneparameter includes at least one parameter selected from the groupconsisting of: a fetus blood parameter; an oxygen saturation level ofthe fetus; concentration of a substance or a structure within the fetus;concentration of a substance or a structure within amniotic fluid;presence of meconium in the amniotic fluid and concentration thereof;presence of blood in the amniotic fluid and concentration thereof; and alevel of lung maturity of the fetus; and wherein extracting, from thetagged light portion of the measured data, the data portion associatedwith the light response of the region of interest comprises facilitatingmonitoring of the selected parameter.
 67. The method of claim 65,wherein said at least one parameter includes the level of lung maturityof the fetus, the method further comprising determining presence andconcentration of lamellar bodies in the amniotic fluid, based upon theextracted data portion.
 68. The method of claim 39, wherein extracting,from the tagged light portion of the measured data, the data portionassociated with the light response of the region of interest comprisesfacilitating monitoring optical properties of an extravascular fluidselected from the group consisting of: pleural fluid, pericardial fluid,peritoneal fluid and synovial fluid.
 69. A method for use in noninvasivemonitoring oxygen saturation level, the method comprising: applyingultrasound tagging of light in pulse oxymetric measurements, obtainingmeasured data indicative of variations of collected light as a functionof both time and wavelength of illuminating light, the collected lightincluding scattered light having ultrasound tagged and untagged lightportions, interpreting the tagged light portions as having been at leastpartially scattered by a region of interest, interpreting the untaggedlight portions as having been scattered by a region outside of theregion of interest, and extracting, from the tagged light portion of themeasured data, the data portion associated with the light response ofthe region of interest, based on the untagged light portion of themeasured data, and analyzing the data portion associated with the lightresponse of the region of interest to calculate the oxygen saturationlevel of the region of interest.
 70. A method for use in noninvasivemonitoring at least one parameter of a fetus-related region of interest,the method comprising: providing an optical unit having an illuminationassembly configured to define at least one output port for theilluminating light; and a light detection assembly configured to defineat least one light input port for collecting light, and to generatemeasured data indicative of the collected light; and providing anacoustic unit configured to generate acoustic waves of a predeterminedultrasound frequency range; providing an optimal positioning of theoptical and acoustic units with respect to each other and with respectto the fetus-related region of interest, said optimal positioningsatisfying an operating condition resulting in that the ultrasound wavesof the predetermined frequency range overlap with the illuminating lightwithin the fetus-related region of interest, while substantially notoverlapping in a maternal tissues region outside the fetus-relatedregion of interest, and in that the detection assembly collects lightscattered from the fetus-related region of interest and from thematernal tissues region; operating the optical and acoustic units, whenin the optimal positioning, and generating measured data indicative ofcollected light including scattered light having ultrasound tagged anduntagged light portions, interpreting the tagged light portions ashaving been at least partially scattered by the fetus-related region ofinterest, interpreting the untagged light portions as having beenscattered by the maternal tissues region outside of the fetus-relatedregion of interest, and extracting, from the tagged light portion of themeasured data, the data portion associated with the light response ofthe fetus-related region of interest, based on the untagged lightportions of the measured data.
 71. The method of claim 70, whereinextracting, from the tagged light portion of the measured data, the dataportion associated with the light response of the fetus-related regionof interest comprises extracting, from the tagged light portion of themeasured data, the data portion associated with the light response ofthe fetus-related region of interest selected from the group consistingof: a fetus-related region of interest containing the fetus only, and afetus-related region of interest containing the fetus and amniotic fluidregions.
 72. The method of claim 71, wherein said at least one parameterincludes at least one parameter selected from the group consisting ofoxygen saturation level, and concentration of a substance in the fetusregion, and concentration of a structure in the fetus region, andwherein extracting, from the tagged light portion of the measured data,the data portion associated in the light response of the fetus-relatedregion of interest comprises facilitating monitoring of the selectedparameter.
 73. The method of claim 72, wherein said at least oneparameter includes at least one parameter selected from the groupconsisting: a level of lung maturity of the fetus; presence of lamellarbodies; concentration of lamellar bodies; presence of meconium;concentration of meconium; presence of blood; and concentration ofblood, and wherein extracting, from the tagged light portion of themeasured data, the data portion associated in the light response of thefetus-related region of interest comprises facilitating monitoring ofthe selected parameter.